Biogerontology (2014) 15:13–19 DOI 10.1007/s10522-013-9475-y
REVIEW ARTICLE
The role of mitochondria in age-related hearing loss Hengchao Chen • Jianguo Tang
Received: 19 June 2013 / Accepted: 21 October 2013 / Published online: 8 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Age-related hearing loss (ARHL), the hearing loss associated with aging, is a vital problem in present society. The severity of hearing loss is possibly associated with the degeneration of cochlear cells. Mitochondria play a key role in the energy supply, cellular redox homeostasis, signaling, and regulation of programmed cell death. In this review, we focus on the central role of mitochondria in ARHL. The mitochondrial redox imbalance and mitochondrial DNA mutation might collaboratively involve in the process of cochlear senescence in response to the aging stress. Subsequent responses, including alteration of mitochondrial biogenesis, mitophagy, apoptosis and paraptosis, participate in the aging process from different respects. Keywords Age-related hearing loss Mitochondria Oxidative stress Mitochondrial DNA
Introduction Age-related hearing loss (ARHL), also known as presbycusis, is the gradually progressive loss of
H. Chen J. Tang (&) Department of Otolaryngology-Head and Neck Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou 310016, China e-mail: [email protected]
hearing associated with aging. In addition to deafness, patients may have difficulty in understanding rapidly spoken language, and speech within a noisy, distracting environment. With the growth of aged population, ARHL places a huge burden on families and society. Roughly 25–30 % of Americans aged 65–74 years are estimated to suffer the impaired hearing. Furthermore, the prevalence rises with age. Approximately 30 % of men and 20 % of women in Europe have been found to suffer a hearing loss of 30 dB HL or more by 70 years of age, and 55 % of men and 45 % of women by 80 years of age (Roth et al. 2011). The major cause of adult-onset hearing loss is ARHL, and ARHL is more prevalent in men than women for every decade younger than 80 years (Gopinath et al. 2009). The accurate incidence of ARHL in China is unavailable. In the second national sample survey for disabled persons, the prevalence rate of hearing loss in Chinese by 60 years of age or older was 11.04 %. The hearing loss of aged people was mainly due to ARHL, accounting for 66.87 %. Large quantity of research has been conducted to ascertain the exact causes of ARHL, such as heritability, environmental factors, and medical conditions, which has been reviewed previously (Huang and Tang 2010). However, the exact pathophysiological mechanisms are not fully clarified yet. Mitochondria, described as ‘‘cellular power plants’’, catalyze the phosphorylation of cellular ADP to ATP and supply energy. In addition, mitochondria play a key role in the cellular redox homeostasis, signaling,
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and regulation of programmed cell death. Age-related mitochondrial changes may disturb a series of cellular physiological functions, and contribute to the development of age-related disease, such as Alzheimer’s disease, type 2 diabetes mellitus and ARHL. The present paper aims to review the research and finding of the last several years in order to outline a general framework to understand the role of mitochondria in ARHL.
Age-related redox imbalance in mitochondria contributes to ARHL Mitochondria are the major source of ROS, the representative of oxidative stress, which mainly arise either from leakage during the mitochondrial electron transport chain (ETC). ROS are hypothesized to damage key cellular components, such as nuclear and mitochondrial DNA (mtDNA), membranes, and proteins. Normally, mitochondrial and cytosolic antioxidant systems can neutralize excess mitochondrial ROS. Mitochondria-derived ROS is directed towards the matrix, where manganese-dependent SOD (MnSOD, also known as SOD2), the only SOD present, catalyses dismutation into H2O2. Then mitochondrialocalized glutathione peroxidase-1 (GPx-1) and reduced glutathione (GSH) systems, as well as peroxiredoxins (Prx3 or Prx5) and thioredoxin 2 (Trx2) systems reduce H2O2 into water (Handy and Loscalzo 2012). However, in the process of senescence, the accumulation of mtDNA mutations, impairment of oxidative phosphorylation and alteration in the expression of antioxidant enzymes cause the further overproduction of ROS (Wang et al. 2013), which are thought to play a central role in ARHL. Evidence shows ROS increase in the process of senescence of cochlea. In animal models, the markers of oxidative stress increased with age in the cochlea of male CBA/J mice (Jiang et al. 2007). However, overexpression of mitochondria-localized catalase, which can eliminate ROS in mitochondria, lowered the mean ABR hearing thresholds of middle-aged mice at all frequencies, compared with those of agematched wild-type mice. That, in turn, implied that ROS played a causal role in the senescence of cochlea (Someya et al. 2009). The production of ROS in ARHL possibly is different from in natural aging process. ROS levels in plasma is significantly positive
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correlative with pure tone average of low frequencies after adjusting for variables in humans (Hwang et al. 2012). Low serum level of melatonin, one kind of ROS scavengers, is significant in the development of high frequency hearing loss in the elderly (Lasisi and Fehintola 2011). However, it still lacks direct evidences from the cochlea of ARHL individuals. Decreased mitochondrial antioxidant defenses will increase the susceptibility of cochlea to oxidative stress in the process of senescence. The age-related alteration of antioxidant enzymes differs from gene level to enzyme level. A certain genetic variation in SOD2 is possibly associated with ARHL. Recently, evidence from the London ARHL cohort suggested males homozygous for the allele, -38C[G, might have a higher risk of ARHL, particularly with a strong family history. Unfortunately, the association failed to replicate in the full ELSA cohort, partly because of its poor diagnostic criteria (Nolan et al. 2013). Another cohort study linked the GSTT1 mutant alleles with the high-frequency steeply sloping audiometric pattern in ARHL patients (Angeli et al. 2012). Moreover, the age-related alteration in the expression of antioxidant enzymes may play an important role in the process of cochlear senescence. A significant age-related down-regulation of 1 gene and up-regulation of 12 genes is reported in the Fischer 344/NHsd rat cochlea. And some up-regulated genes, such as Cygb gene, showed the strongest linear correlation with hearing measurements (ABR/DPOAE), which might play an important in ARHL (Tanaka et al. 2012). Response to senescence, Prx3 revealed a transient increase in mouse cochlear before any hair cells (HCs) loss occurred, where agerelated inhibited cytosolic protein synthesis or accelerated degradation might involve in the change (Chen et al. 2013). Jiang et al. (2007) showed elevated SOD2 mRNAlevel and decreased SOD2 with aging in the organ of Corti and spiral ganglion cells (SGNs), which implied particular vulnerability of mitochondrial proteins, compromised antioxidant capacity, and more importantly mitochondria-localized antioxidant gene circuits in aging cochlea. Moreover, an increase of SOD2 expression gradient in ganglion cells was detected along the basal to apical turn of rodent and primate cochlea (Ying and Balaban 2009), which was consistent with the differential vulnerability of high frequency region in most ARHL, indicating its pathophysiologic basis. In addition, several studies attempt to prevent or ameliorate ARHL by exogenous antioxidant supplementation. However, the results are paradoxical, as
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some gave the prominent benefits (Someya et al. 2009; Seidman 2000; Le and Keithley 2007; Takumida and Anniko 2009; Heman-Ackah et al. 2010), but others didn’t show any effect (Davis et al. 2007; Bielefeld et al. 2008; Sha et al. 2012). The opposite outcomes in these studies may be due to difference in the dosage levels, treatment durations, metabolic mechanisms, genetic background or exposure to excessive noise.
Mitochondrial DNA mutation in ARHL Different from nuclear DNA, mtDNA is frequently undergoing replication, relatively independent of the cell cycle. Furthermore, mtDNA is particularly sensitive to oxidative damage because of the lack of protective histones. The mtDNA mutations will accumulate and expand with advanced age, thus contributing to age-related diseases. And evidence shows mtDNA mutations and mitochondrial dysfunction are involved in the aging and age-related diseases such as neurodegenerative diseases, heart failure, diabetes and cancers (Taylor and Turnbull 2005). Moreover, some age-related conditions are epidemiologically linked with hearing loss. A meta-analysis suggests that higher prevalence of hearing loss is in diabetic patients, regardless of age (Horikawa et al. 2013). Among young adults in southwestern Finland, about 1 % of all diabetes was associated with the m.3243A[G mutation, and all of whom had severe hearing impairment (Martikainen et al. 2012). MtDNA mutations comprise point mutations, insertions and deletions. In archival human cochlear tissue, one of the best-described mtDNA mutations, the mtDNA 4,977 bp or common deletion is associated with ARHL (Bai et al. 1997). Common deletion, a large-scale deletion, spans from position 8470 to position 13447 on the human mtDNA, where the genes encoding four complex I subunits (ND3–ND5, ND 4L), one complex IV subunit (COIII), two complex V subunits (ATPase 6, ATPase 8) and five tRNA genes. Other large-scale mtDNA deletions, the 5,354 bp deletion, 9,682 bp deletion and 5,142 bp deletion, also have been identified in archival human temporal bones (Markaryan et al. 2008a). All three of these deletions involve the complex IV subunit (COIII) gene, encoded in the major arc of the mtDNA genome, which is an essential component in mitochondrial
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energy metabolism. Temporal bone analysis revealed increased mtDNA deletions and mutations in some individuals with ARHL (Fischel-Ghodsian et al. 1997). Quantitative analysis of the mtDNA in archival cochlear tissue samples determined a mean common deletion level of 32 ± 14 % in the ARHL group, compared with level of 12 ± 2 % from a normal hearing age-matched group, and established a significant correlation between the common deletion level in human cochlear tissue and the severity of hearing loss (Markaryan et al. 2009). The distribution of mtDNA deletions is non-uniform in the different cochlear elements (Markaryan et al. 2008a), and even in the different individual SGNs from the same ARHL patient. In an individual with ARHL, the 5,142 and 5,354 bp deletions existed in the organ of corti, spiral ligament, and ganglion cells, but not in the stria vascularis (Markaryan et al. 2008b). Krishnan et al. (2008) reviewed abundant evidence, and concluded that the mtDNA repair possibly triggered the primary formation of large-scale mtDNA deletions, through exonuclease activity at double-strand breaks within the single-stranded regions of mtDNA. However, the actual mechanism of DNA repair in mitochondria is still poorly understood. In addition, by analysis of temporal bones, the hypoxia of cochlea resulting from the stenosis of vasa nervorum was possibly related to the elevated common deletion level (Pu et al. 2004). As mentioned above, 4,977, 5,354, 9,682 and 5,142 bp deletion all affect the expression of COIII gene, involved in the disturbance of ETC. The consequence of mtDNA deletions is deficits in energy metabolism. Markaryan et al. (2010) determined the expression of COIII decreased in SGNs from humans with ARHL, suggesting that deficits in the ETC of SGNs may contribute to the hearing loss in ARHL. However, any of these mtDNA deletions seem to become clinically apparent only when a threshold level is exceeded. And the threshold level could vary among the cochlear elements. As for mitochondrial variants, although continuously identified association with noise-induced hearing loss (Abreu-Silva et al. 2011), aminoglycosideinduced hearing loss (Lu et al. 2010; Dowlati et al. 2013) and nonsyndromic hearing loss (Vivero et al. 2012), there is no evidence that inherited mitochondrial variants contribute to increased ARHL susceptibility (Bonneux et al. 2011), which should be regarded with caution and further verified.
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Mitochondrial turnover and ARHL The constant mitochondrial turnover is crucial for maintaining normal function of mitochondria with age, especially for the post-mitotic nature of cells in cochlea. Two key processes, mitochondrial biogenesis and selective degradation (mitophagy), jointly participate in mitochondrial turnover. In the SGNs of senescence-accelerated prone mouse 8 (SAMP8), mitochondrial biogenesis, characterized by ratio of mtDNA/nuclear DNA and activity of citrate synthase, increased at young age and decreased at old age, quite opposite to the senescence-accelerated resistant mice 1 (SAMR1), which suggested cells attempted to maintain normal mitochondrial function by strong early but limited stimulation of mitochondrial biogenesis (Menardo et al. 2012). The key regulator of mitochondrial biogenesis is peroxisome proliferator-activated receptor c coactivator a (PGC-1a), whose age-related reductions itself and tissue-specific function might be the important contributing factors to mitochondrial function in age-related diseases (Wenz 2011). In the auditory cortex of aged mice, responding to the signal stimulated by mtDNA damage and decline in the cytochrome c oxidase activity, compensatory increases of PGC-1a and its downstream signal mediator emerged (Zhong et al. 2012). Even with insufficient knowledge of mitochondrial biogenesis in age-related cochlear change, PGC-1a sheds some lights on the better understanding for mitochondrial dysfunction in ARHL. For example, the overexpression of PGC-1a with consequent increase of NRF1 and TFAM significantly decreased the accumulation of damaged mtDNA and the number of apoptotic cells in the strial marginal cells senescence model (Zhao et al. 2013). Autophagy is the process whereby cell degrades its unnecessary or dysfunctional cellular components through lysosomes, and mitophagy is the selective degradation for mitochondria. In the SGNs of SAMP8, early up-regulated autophagy, autophagic vacuoles and lipofuscin accumulation were observed, compared with age-matched SAMR1. Autophagy might promote survival of SGNs in young SAMP8 cochlea as well, but triggered the SGNs death when beyond of control (Menardo et al. 2012). Morever, down-regulation of mitophagy will result in abnormal mitochondrial morphology. Normally, mitophagy participates in
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cleaning dysfunctional mitochondria, coming from constant mitochondrial fission, by which the detrimental mtDNA mutation can be eliminated. Together with mitochondrial biogenesis, mitophagy maintains a dynamic balance between mitochondria fission and fusion, which also known as mitochondrial dynamics. However, down-regulation of mitochondrial fission and impairment of mitophagy might result in the formation of giant mitochondria, characterized by loss of cristae structure and a swollen morphology (Seo et al. 2010), which were observed in the cochlear structures of the senescence-accelerated CD/1 mice (Mahendrasingam et al. 2011). Because of imbalance of mitochondrial dynamics, accumulation of abnormal function and shape of mitochondria accelerates the apoptosis (Seo et al. 2010), which should be further elucidated in the senescence cochlea.
Mitochondrial apoptosis and ARHL Apoptosis can be triggered by either intrinsic or extrinsic pathway. The intrinsic pathway, known as the mitochondrial pathway, is initiated with the loss of outer mitochondrial membrane integrity. Complicated cell death pathways participate in ARHL, and apoptosis are observed as the major type of outer HCs death in the aging CBA/J mice (Sha et al. 2009). By GeneChip and real-time PCR microarrays, Tadros et al. (2008) revealed the changes of apoptosis-related gene expression with aging in the CBA mouse cochlea. Expressions of anti-apoptotic members, Bcl-xL and Bcl2, were highly correlated with aging, which suggested an inhibited mitochondrial apoptosis response to increased age-related oxidative stress. Someya et al. (2009) revealed a mitochondrialocalized Bak-dependent apoptosis in the cochlear cells induced by oxidative stress. In HeLa cells, the Bak-dependent mitochondrial apoptosis are promoted by expression of Sirt3, a mitochondria-localized sirtuin (Verma et al. 2013). Paradoxically, in response to caloric restriction (CR), elevated Sirt3 could promote cochlear cellular survival by directly deacetylating and activating mitochondrial isocitrate dehydrogenase 2 (Idh2), leading to increase levels of reduced glutathione and effect of hearing reservation (Someya et al. 2010). Tissue-specific manner of Sirt3 might involve in the aging cochlea. In addition, the
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Fig. 1 A conceptual figure for mitochondria-centered development of AHRL
downstream cyclophilin-D and hexokinase, the key of Bak-dependent apoptosis and necrosis (Verma et al. 2013), should be further elucidated in the cochlear tissue. Another far from confirmed pro-apoptotic molecular, p66shc, biologically active when stranslocation from cytosol to the mitochondrial intermembrane space, might induce apoptosis by cytochrome c release and future ROS formation in responding to oxidative stress (Pani and Galeotti 2011). Wu et al. (2012) showed that the mRNA and protein levels of p66shc significantly increased within the lateral wall of cochlea from 10 weeks D-gal-induced aging mice. Besides, the inhibitive effect of active p66shc on SOD2 also needs further exploration. Moreover, paraptosis, a novel alternative model of cell death, is characterized by cytoplasmic vacuolization and mitochondrial swelling without caspase activation or typical nuclear changes. Similar morphological alterations of outer HCs are observed in aged Mpv17-/- mice, in which the absence of Mpv17 encoded mitochondrial inner membrane protein leads to degenerative sensorineural hearing loss (Meyer zum Gottesberge et al. 2012).
Conclusions ARHL is one of the most common sensory disorders in the elderly population. Mitochondria are the key of energy supply, biosynthesis and intrinsic apoptosis of cells in the inner ear, particularly in the vulnerable or higher energy-consuming cells, such as HCs and SGNs. The severity of hearing loss is possibly associated with the degeneration of cochlear cells (Nelson and Hinojosa 2006), and a mitochondriacentered pathophysiological mechanisms might play an important role in the process of cochlear senescence. It is postulated that mitochondrial redox imbalance and mtDNA damage collaboratively involve in subsequent process of cochlear senescence in response to the aging stress, and a conceptual figure for mitochondria-centered development of AHRL has been shown in Fig. 1. However, the caution should be drawn into consideration that most results coming from animal model lack of representation and ARHL per se differs from the natural aging process of cochlea (Bo¨ttger and Schacht 2013). Moreover, we do not exclude other mechanisms, because ARHL is a
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multifactorial process. For example, NOX3 are highly expressed on the cellular membrane in the auditory system. Despite lack of compact laboratory proofs, NOX3 is still considered a key role in the pathogenesis of ARHL (Krause 2007; Rybak et al. 2012).
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REVIEW ARTICLE
The role of mitochondria in age-related hearing loss Hengchao Chen • Jianguo Tang
Received: 19 June 2013 / Accepted: 21 October 2013 / Published online: 8 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Age-related hearing loss (ARHL), the hearing loss associated with aging, is a vital problem in present society. The severity of hearing loss is possibly associated with the degeneration of cochlear cells. Mitochondria play a key role in the energy supply, cellular redox homeostasis, signaling, and regulation of programmed cell death. In this review, we focus on the central role of mitochondria in ARHL. The mitochondrial redox imbalance and mitochondrial DNA mutation might collaboratively involve in the process of cochlear senescence in response to the aging stress. Subsequent responses, including alteration of mitochondrial biogenesis, mitophagy, apoptosis and paraptosis, participate in the aging process from different respects. Keywords Age-related hearing loss Mitochondria Oxidative stress Mitochondrial DNA
Introduction Age-related hearing loss (ARHL), also known as presbycusis, is the gradually progressive loss of
H. Chen J. Tang (&) Department of Otolaryngology-Head and Neck Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou 310016, China e-mail: [email protected]
hearing associated with aging. In addition to deafness, patients may have difficulty in understanding rapidly spoken language, and speech within a noisy, distracting environment. With the growth of aged population, ARHL places a huge burden on families and society. Roughly 25–30 % of Americans aged 65–74 years are estimated to suffer the impaired hearing. Furthermore, the prevalence rises with age. Approximately 30 % of men and 20 % of women in Europe have been found to suffer a hearing loss of 30 dB HL or more by 70 years of age, and 55 % of men and 45 % of women by 80 years of age (Roth et al. 2011). The major cause of adult-onset hearing loss is ARHL, and ARHL is more prevalent in men than women for every decade younger than 80 years (Gopinath et al. 2009). The accurate incidence of ARHL in China is unavailable. In the second national sample survey for disabled persons, the prevalence rate of hearing loss in Chinese by 60 years of age or older was 11.04 %. The hearing loss of aged people was mainly due to ARHL, accounting for 66.87 %. Large quantity of research has been conducted to ascertain the exact causes of ARHL, such as heritability, environmental factors, and medical conditions, which has been reviewed previously (Huang and Tang 2010). However, the exact pathophysiological mechanisms are not fully clarified yet. Mitochondria, described as ‘‘cellular power plants’’, catalyze the phosphorylation of cellular ADP to ATP and supply energy. In addition, mitochondria play a key role in the cellular redox homeostasis, signaling,
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and regulation of programmed cell death. Age-related mitochondrial changes may disturb a series of cellular physiological functions, and contribute to the development of age-related disease, such as Alzheimer’s disease, type 2 diabetes mellitus and ARHL. The present paper aims to review the research and finding of the last several years in order to outline a general framework to understand the role of mitochondria in ARHL.
Age-related redox imbalance in mitochondria contributes to ARHL Mitochondria are the major source of ROS, the representative of oxidative stress, which mainly arise either from leakage during the mitochondrial electron transport chain (ETC). ROS are hypothesized to damage key cellular components, such as nuclear and mitochondrial DNA (mtDNA), membranes, and proteins. Normally, mitochondrial and cytosolic antioxidant systems can neutralize excess mitochondrial ROS. Mitochondria-derived ROS is directed towards the matrix, where manganese-dependent SOD (MnSOD, also known as SOD2), the only SOD present, catalyses dismutation into H2O2. Then mitochondrialocalized glutathione peroxidase-1 (GPx-1) and reduced glutathione (GSH) systems, as well as peroxiredoxins (Prx3 or Prx5) and thioredoxin 2 (Trx2) systems reduce H2O2 into water (Handy and Loscalzo 2012). However, in the process of senescence, the accumulation of mtDNA mutations, impairment of oxidative phosphorylation and alteration in the expression of antioxidant enzymes cause the further overproduction of ROS (Wang et al. 2013), which are thought to play a central role in ARHL. Evidence shows ROS increase in the process of senescence of cochlea. In animal models, the markers of oxidative stress increased with age in the cochlea of male CBA/J mice (Jiang et al. 2007). However, overexpression of mitochondria-localized catalase, which can eliminate ROS in mitochondria, lowered the mean ABR hearing thresholds of middle-aged mice at all frequencies, compared with those of agematched wild-type mice. That, in turn, implied that ROS played a causal role in the senescence of cochlea (Someya et al. 2009). The production of ROS in ARHL possibly is different from in natural aging process. ROS levels in plasma is significantly positive
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correlative with pure tone average of low frequencies after adjusting for variables in humans (Hwang et al. 2012). Low serum level of melatonin, one kind of ROS scavengers, is significant in the development of high frequency hearing loss in the elderly (Lasisi and Fehintola 2011). However, it still lacks direct evidences from the cochlea of ARHL individuals. Decreased mitochondrial antioxidant defenses will increase the susceptibility of cochlea to oxidative stress in the process of senescence. The age-related alteration of antioxidant enzymes differs from gene level to enzyme level. A certain genetic variation in SOD2 is possibly associated with ARHL. Recently, evidence from the London ARHL cohort suggested males homozygous for the allele, -38C[G, might have a higher risk of ARHL, particularly with a strong family history. Unfortunately, the association failed to replicate in the full ELSA cohort, partly because of its poor diagnostic criteria (Nolan et al. 2013). Another cohort study linked the GSTT1 mutant alleles with the high-frequency steeply sloping audiometric pattern in ARHL patients (Angeli et al. 2012). Moreover, the age-related alteration in the expression of antioxidant enzymes may play an important role in the process of cochlear senescence. A significant age-related down-regulation of 1 gene and up-regulation of 12 genes is reported in the Fischer 344/NHsd rat cochlea. And some up-regulated genes, such as Cygb gene, showed the strongest linear correlation with hearing measurements (ABR/DPOAE), which might play an important in ARHL (Tanaka et al. 2012). Response to senescence, Prx3 revealed a transient increase in mouse cochlear before any hair cells (HCs) loss occurred, where agerelated inhibited cytosolic protein synthesis or accelerated degradation might involve in the change (Chen et al. 2013). Jiang et al. (2007) showed elevated SOD2 mRNAlevel and decreased SOD2 with aging in the organ of Corti and spiral ganglion cells (SGNs), which implied particular vulnerability of mitochondrial proteins, compromised antioxidant capacity, and more importantly mitochondria-localized antioxidant gene circuits in aging cochlea. Moreover, an increase of SOD2 expression gradient in ganglion cells was detected along the basal to apical turn of rodent and primate cochlea (Ying and Balaban 2009), which was consistent with the differential vulnerability of high frequency region in most ARHL, indicating its pathophysiologic basis. In addition, several studies attempt to prevent or ameliorate ARHL by exogenous antioxidant supplementation. However, the results are paradoxical, as
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some gave the prominent benefits (Someya et al. 2009; Seidman 2000; Le and Keithley 2007; Takumida and Anniko 2009; Heman-Ackah et al. 2010), but others didn’t show any effect (Davis et al. 2007; Bielefeld et al. 2008; Sha et al. 2012). The opposite outcomes in these studies may be due to difference in the dosage levels, treatment durations, metabolic mechanisms, genetic background or exposure to excessive noise.
Mitochondrial DNA mutation in ARHL Different from nuclear DNA, mtDNA is frequently undergoing replication, relatively independent of the cell cycle. Furthermore, mtDNA is particularly sensitive to oxidative damage because of the lack of protective histones. The mtDNA mutations will accumulate and expand with advanced age, thus contributing to age-related diseases. And evidence shows mtDNA mutations and mitochondrial dysfunction are involved in the aging and age-related diseases such as neurodegenerative diseases, heart failure, diabetes and cancers (Taylor and Turnbull 2005). Moreover, some age-related conditions are epidemiologically linked with hearing loss. A meta-analysis suggests that higher prevalence of hearing loss is in diabetic patients, regardless of age (Horikawa et al. 2013). Among young adults in southwestern Finland, about 1 % of all diabetes was associated with the m.3243A[G mutation, and all of whom had severe hearing impairment (Martikainen et al. 2012). MtDNA mutations comprise point mutations, insertions and deletions. In archival human cochlear tissue, one of the best-described mtDNA mutations, the mtDNA 4,977 bp or common deletion is associated with ARHL (Bai et al. 1997). Common deletion, a large-scale deletion, spans from position 8470 to position 13447 on the human mtDNA, where the genes encoding four complex I subunits (ND3–ND5, ND 4L), one complex IV subunit (COIII), two complex V subunits (ATPase 6, ATPase 8) and five tRNA genes. Other large-scale mtDNA deletions, the 5,354 bp deletion, 9,682 bp deletion and 5,142 bp deletion, also have been identified in archival human temporal bones (Markaryan et al. 2008a). All three of these deletions involve the complex IV subunit (COIII) gene, encoded in the major arc of the mtDNA genome, which is an essential component in mitochondrial
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energy metabolism. Temporal bone analysis revealed increased mtDNA deletions and mutations in some individuals with ARHL (Fischel-Ghodsian et al. 1997). Quantitative analysis of the mtDNA in archival cochlear tissue samples determined a mean common deletion level of 32 ± 14 % in the ARHL group, compared with level of 12 ± 2 % from a normal hearing age-matched group, and established a significant correlation between the common deletion level in human cochlear tissue and the severity of hearing loss (Markaryan et al. 2009). The distribution of mtDNA deletions is non-uniform in the different cochlear elements (Markaryan et al. 2008a), and even in the different individual SGNs from the same ARHL patient. In an individual with ARHL, the 5,142 and 5,354 bp deletions existed in the organ of corti, spiral ligament, and ganglion cells, but not in the stria vascularis (Markaryan et al. 2008b). Krishnan et al. (2008) reviewed abundant evidence, and concluded that the mtDNA repair possibly triggered the primary formation of large-scale mtDNA deletions, through exonuclease activity at double-strand breaks within the single-stranded regions of mtDNA. However, the actual mechanism of DNA repair in mitochondria is still poorly understood. In addition, by analysis of temporal bones, the hypoxia of cochlea resulting from the stenosis of vasa nervorum was possibly related to the elevated common deletion level (Pu et al. 2004). As mentioned above, 4,977, 5,354, 9,682 and 5,142 bp deletion all affect the expression of COIII gene, involved in the disturbance of ETC. The consequence of mtDNA deletions is deficits in energy metabolism. Markaryan et al. (2010) determined the expression of COIII decreased in SGNs from humans with ARHL, suggesting that deficits in the ETC of SGNs may contribute to the hearing loss in ARHL. However, any of these mtDNA deletions seem to become clinically apparent only when a threshold level is exceeded. And the threshold level could vary among the cochlear elements. As for mitochondrial variants, although continuously identified association with noise-induced hearing loss (Abreu-Silva et al. 2011), aminoglycosideinduced hearing loss (Lu et al. 2010; Dowlati et al. 2013) and nonsyndromic hearing loss (Vivero et al. 2012), there is no evidence that inherited mitochondrial variants contribute to increased ARHL susceptibility (Bonneux et al. 2011), which should be regarded with caution and further verified.
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Mitochondrial turnover and ARHL The constant mitochondrial turnover is crucial for maintaining normal function of mitochondria with age, especially for the post-mitotic nature of cells in cochlea. Two key processes, mitochondrial biogenesis and selective degradation (mitophagy), jointly participate in mitochondrial turnover. In the SGNs of senescence-accelerated prone mouse 8 (SAMP8), mitochondrial biogenesis, characterized by ratio of mtDNA/nuclear DNA and activity of citrate synthase, increased at young age and decreased at old age, quite opposite to the senescence-accelerated resistant mice 1 (SAMR1), which suggested cells attempted to maintain normal mitochondrial function by strong early but limited stimulation of mitochondrial biogenesis (Menardo et al. 2012). The key regulator of mitochondrial biogenesis is peroxisome proliferator-activated receptor c coactivator a (PGC-1a), whose age-related reductions itself and tissue-specific function might be the important contributing factors to mitochondrial function in age-related diseases (Wenz 2011). In the auditory cortex of aged mice, responding to the signal stimulated by mtDNA damage and decline in the cytochrome c oxidase activity, compensatory increases of PGC-1a and its downstream signal mediator emerged (Zhong et al. 2012). Even with insufficient knowledge of mitochondrial biogenesis in age-related cochlear change, PGC-1a sheds some lights on the better understanding for mitochondrial dysfunction in ARHL. For example, the overexpression of PGC-1a with consequent increase of NRF1 and TFAM significantly decreased the accumulation of damaged mtDNA and the number of apoptotic cells in the strial marginal cells senescence model (Zhao et al. 2013). Autophagy is the process whereby cell degrades its unnecessary or dysfunctional cellular components through lysosomes, and mitophagy is the selective degradation for mitochondria. In the SGNs of SAMP8, early up-regulated autophagy, autophagic vacuoles and lipofuscin accumulation were observed, compared with age-matched SAMR1. Autophagy might promote survival of SGNs in young SAMP8 cochlea as well, but triggered the SGNs death when beyond of control (Menardo et al. 2012). Morever, down-regulation of mitophagy will result in abnormal mitochondrial morphology. Normally, mitophagy participates in
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cleaning dysfunctional mitochondria, coming from constant mitochondrial fission, by which the detrimental mtDNA mutation can be eliminated. Together with mitochondrial biogenesis, mitophagy maintains a dynamic balance between mitochondria fission and fusion, which also known as mitochondrial dynamics. However, down-regulation of mitochondrial fission and impairment of mitophagy might result in the formation of giant mitochondria, characterized by loss of cristae structure and a swollen morphology (Seo et al. 2010), which were observed in the cochlear structures of the senescence-accelerated CD/1 mice (Mahendrasingam et al. 2011). Because of imbalance of mitochondrial dynamics, accumulation of abnormal function and shape of mitochondria accelerates the apoptosis (Seo et al. 2010), which should be further elucidated in the senescence cochlea.
Mitochondrial apoptosis and ARHL Apoptosis can be triggered by either intrinsic or extrinsic pathway. The intrinsic pathway, known as the mitochondrial pathway, is initiated with the loss of outer mitochondrial membrane integrity. Complicated cell death pathways participate in ARHL, and apoptosis are observed as the major type of outer HCs death in the aging CBA/J mice (Sha et al. 2009). By GeneChip and real-time PCR microarrays, Tadros et al. (2008) revealed the changes of apoptosis-related gene expression with aging in the CBA mouse cochlea. Expressions of anti-apoptotic members, Bcl-xL and Bcl2, were highly correlated with aging, which suggested an inhibited mitochondrial apoptosis response to increased age-related oxidative stress. Someya et al. (2009) revealed a mitochondrialocalized Bak-dependent apoptosis in the cochlear cells induced by oxidative stress. In HeLa cells, the Bak-dependent mitochondrial apoptosis are promoted by expression of Sirt3, a mitochondria-localized sirtuin (Verma et al. 2013). Paradoxically, in response to caloric restriction (CR), elevated Sirt3 could promote cochlear cellular survival by directly deacetylating and activating mitochondrial isocitrate dehydrogenase 2 (Idh2), leading to increase levels of reduced glutathione and effect of hearing reservation (Someya et al. 2010). Tissue-specific manner of Sirt3 might involve in the aging cochlea. In addition, the
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Fig. 1 A conceptual figure for mitochondria-centered development of AHRL
downstream cyclophilin-D and hexokinase, the key of Bak-dependent apoptosis and necrosis (Verma et al. 2013), should be further elucidated in the cochlear tissue. Another far from confirmed pro-apoptotic molecular, p66shc, biologically active when stranslocation from cytosol to the mitochondrial intermembrane space, might induce apoptosis by cytochrome c release and future ROS formation in responding to oxidative stress (Pani and Galeotti 2011). Wu et al. (2012) showed that the mRNA and protein levels of p66shc significantly increased within the lateral wall of cochlea from 10 weeks D-gal-induced aging mice. Besides, the inhibitive effect of active p66shc on SOD2 also needs further exploration. Moreover, paraptosis, a novel alternative model of cell death, is characterized by cytoplasmic vacuolization and mitochondrial swelling without caspase activation or typical nuclear changes. Similar morphological alterations of outer HCs are observed in aged Mpv17-/- mice, in which the absence of Mpv17 encoded mitochondrial inner membrane protein leads to degenerative sensorineural hearing loss (Meyer zum Gottesberge et al. 2012).
Conclusions ARHL is one of the most common sensory disorders in the elderly population. Mitochondria are the key of energy supply, biosynthesis and intrinsic apoptosis of cells in the inner ear, particularly in the vulnerable or higher energy-consuming cells, such as HCs and SGNs. The severity of hearing loss is possibly associated with the degeneration of cochlear cells (Nelson and Hinojosa 2006), and a mitochondriacentered pathophysiological mechanisms might play an important role in the process of cochlear senescence. It is postulated that mitochondrial redox imbalance and mtDNA damage collaboratively involve in subsequent process of cochlear senescence in response to the aging stress, and a conceptual figure for mitochondria-centered development of AHRL has been shown in Fig. 1. However, the caution should be drawn into consideration that most results coming from animal model lack of representation and ARHL per se differs from the natural aging process of cochlea (Bo¨ttger and Schacht 2013). Moreover, we do not exclude other mechanisms, because ARHL is a
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multifactorial process. For example, NOX3 are highly expressed on the cellular membrane in the auditory system. Despite lack of compact laboratory proofs, NOX3 is still considered a key role in the pathogenesis of ARHL (Krause 2007; Rybak et al. 2012).
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