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Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations夽
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Valerio Carellia,b,∗ , Alessandra Marescaa,b , Leonardo Caporalia,b , Selena Trifunovc,b , Claudia Zannaa,c , Michela Rugoloc a
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy c Unit of Cellular Biochemistry, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy b
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Article history: Received 7 November 2014 Received in revised form 20 January 2015 Accepted 29 January 2015 Available online xxx
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Keywords: Mitochondrial DNA Mitochondrial DNA mutations Clonal expansion Mitophagy Nucleoids
Mitochondria are cytoplasmic organelles containing their own multi-copy genome. They are organized in a highly dynamic network, resulting from balance between fission and fusion, which maintains homeostasis of mitochondrial mass through mitochondrial biogenesis and mitophagy. Mitochondrial DNA (mtDNA) mutates much faster than nuclear DNA. In particular, mtDNA point mutations and deletions may occur somatically and accumulate with aging, coexisting with the wild type, a condition known as heteroplasmy. Under specific circumstances, clonal expansion of mutant mtDNA may occur within single cells, causing a wide range of severe human diseases when mutant overcomes wild type. Furthermore, mtDNA deletions accumulate and clonally expand as a consequence of deleterious mutations in nuclear genes involved in mtDNA replication and maintenance, as well as in mitochondrial fusion genes (mitofusin-2 and OPA1), possibly implicating mtDNA nucleoids segregation. We here discuss how the intricacies of mitochondrial homeostasis impinge on the intracellular propagation of mutant mtDNA. This article is part of a Directed Issue entitled: Mitochondrial Diseases. © 2015 Published by Elsevier Ltd. 25 26
Mitochondria facts: • Mitochondria form a highly dynamic network resulting from continuous fission and fusion events. • Homeostasis of mitochondrial mass is maintained by a balance between mitochondrial biogenesis and removal of damaged organelles by mitophagy. • Mitochondria are endowed of a multi-copy genome, the mtDNA, exhibiting a high mutation rate. • MtDNA mutations and deletions are associated with a wide range of human diseases. • Clonal expansion of mutant mtDNA occurs under different conditions and during aging in single cells. • Proteins involved in mitochondrial fusion are crucial for mtDNA maintenance.
夽 This article is part of a Directed Issue entitled: Mitochondrial Diseases. ∗ Corresponding author at: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Via Altura 3, 40139 Bologna, Italy. Tel.: +39 051 4966747; fax: +39 051 4966208. E-mail address: [email protected] (V. Carelli).
1. Introduction Biology of mitochondria and their genetic content, mitochon- Q2 drial DNA (mtDNA), does not obey the Mendelian rules, and remains in many aspects poorly understood. The focus on this organelle has been exponentially growing since the first mtDNA mutations were identified as the cause of neuromuscular diseases in humans, giving birth to the field of “mitochondrial medicine” (Wallace et al., 1988; Holt et al., 1988). The segregation of these mutant mtDNAs along the maternal germline, from one generation to the other, as well as the segregation in tissues during embryonic development and over the individual’s lifespan, both remain hot topics of scientific investigation and debate. In particular, we here consider how the intricacies of mitochondrial homeostasis, including maintenance of mitochondrial dynamics (fission/fusion) and mass (biogenesis/mitophagy) (Fig. 1A), impinge on the propagation within cells of one mutant mtDNA species over the remaining genomes, a phenomenon known as “clonal expansion” of mtDNA mutations (Fig. 1B). This may occur in healthiness, but most importantly in pathology during individual’s lifespan.
http://dx.doi.org/10.1016/j.biocel.2015.01.023 1357-2725/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Carelli V, et al. Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.01.023
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3. Pathology: heteroplasmy and polyplasmy of mtDNA, purifying selection and somatic segregation
Fig. 1. Mitochondrial homeostasis and mechanisms involved in clonal expansion of mutated mtDNA molecules.
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2. Physiology: the mitochondrial life cycle Mitochondria are cytoplasmic organelles carrying their multicopy small circular mDNA, and form a dynamic network resulting from continuous fission (division) and fusion events (Chan, 2012). Balance between fission and fusion is closely related to the homeostatic adjustment of mitochondrial mass to the metabolic needs of different tissues or cells (Mishra et al., 2014). Loss of this balance closely relates to regulation of apoptosis and cell death. Thus, maintenance of mitochondrial homeostasis is determined by mitochondrial biogenesis, which provides newly synthesized organelles, as opposed to autophagic elimination of damaged mitochondria, termed mitophagy (Youle and Narendra, 2011). The latter is mostly contributed by mitochondrial fission, which isolates and signals dysfunctional mitochondria for their removal. One signaling system for mitochondrial removal is the Pink1/Parkin axis, a quality control pathway that senses loss of mitochondrial membrane potential. Thus, Pink1 stabilization on the outer membrane recruits Parkin, activating the formation of the mito-autophagosome, ultimately determining mitophagy (Narendra et al., 2010). Other pathways, such as the newly recognized small GTPase Rheb, which promotes mitophagy in response to high oxidative phosphorylation (OXPHOS) activity (Melser et al., 2013), participate in the homeostatic quality control surveillance on mitochondria (Busch et al., 2014). This counteracts the damage derived from long-term exposure to reactive oxygen species produced by the respiratory chain, a contributor of the faster mtDNA mutation rate compared with nuclear DNA (Wallace, 2013). Deletions and point mutations may occur somatically and accumulate with aging, or may affect mtDNA along the germline, thus becoming maternally inherited. The high rate of variants fixed by descent in the mitochondrial genome is highlighted by the great continent and ethnic specificity of mtDNA haplotypes (Pakendorf et al., 2005).
Given the multi-copy nature of mtDNA, mutations lead to coexistence of mtDNA molecules differing in their sequence, a condition known as heteroplasmy or, if multiple sequences coexist, polyplasmy (Wallace et al., 2013). For a long time mtDNA was considered as a collection of identical genomes of clonal origin, thus, normally mtDNA in cells and tissues was assumed to be homoplasmic (Lightowlers et al., 1997). The improvement of sequencing techniques and the widespread investigation of mtDNA in human and animal tissues brought to realize that heteroplasmy was much more frequent than initially believed, in particular considering aging of postmitotic tissues where mutations accumulate with time (Larsson, 2010; Khrapko et al., 2014). Furthermore, deep sequencing revealed that heteroplasmy is universal and is built by somatic and germline transmitted mutations present at low level (Payne et al., 2013). Maternally transmitted mtDNA mutations undergo rounds of purifying selection each generation (Stewart et al., 2008; Fan et al., 2008), through a bottleneck possibly operating along the female germline, from oogonium to primary oocyte (Jenuth et al., 1996, Wai et al., 2008), to post fertilization in the first cell divisions when mtDNA replication seems to be still dormient (Cree et al., 2008). This counteracts the tendency toward irreversible accumulation of deleterious mutations (Carlson, 2013). During embryonic development mtDNA heteroplasmic mutations segregate by genetic drift into a mosaic cellular pattern as cells divide by mitosis (Howell et al., 2000). However, tissue-specific directional drift also occurs (Jenuth et al., 1997), possibly driven by specific nuclear genes (Battersby et al., 2003). Over lifespan mtDNA mutations accumulate at slow rate in single cells of postmitotic tissues, undergoing stochastic events of clonal expansion when mutant mtDNA prevails over wild type (Elson et al., 2001). This has been first noted for mtDNA deletions in human tissues from elders (Cortopassi and Arnheim, 1990; Cortopassi et al., 1992), supporting the hypothesis that progressive accumulation of mtDNA mutations with age leads to mitochondrial dysfunction at the level of single cells in postmitotic tissues such as skeletal and cardiac muscles and brain, contributing to the aging phenotype (Linneane et al., 1989; Larsson, 2010). The “mutator mouse” model has provided strong support to this hypothesis. In this animal the proofreading activity of mitochondrial polymerase ␥ (Pol␥), the only polymerase replicating mtDNA, is affected by a mutation leaving intact the replication capacity (Trifunovic et al., 2004). This mouse accumulates mtDNA mutations since embryonic development, leading to a progeroid phenotype that recapitulates many features of aging in humans (Trifunovic et al., 2004; Edgar et al., 2009; Ahlqvist et al., 2012).
4. Clonal expansion of mutant mtDNA: mitochondrial dynamics and mtDNA nucleoids Specific circumstances may promote clonal expansion of mutant mtDNA, as in the case of HIV patients under therapy with antiretroviral drugs that interfere with the activity of Pol␥ (Payne et al., 2011). In this case, the cyclic temporary reduction of mtDNA copy number at single-cell level, followed by re-expansion of the mtDNA pool, is thought to produce sub-continuous bottleneck effects with accelerated mtDNA turnover, ultimately promoting clonal expansion of pre-existing mtDNA deletions (Payne et al., 2011). Deletions of mtDNA and variable degrees of mtDNA depletion characterize the pathogenic mechanism of deleterious mutations in POLG and many other genes, involved in mtDNA replication or nucleotide balance, which are associated with a wide range of human diseases, from infantile syndromes such as Alpers-Huttenlocher syndrome to chronic progressive external ophthalmoplegia (CPEO) and late
Please cite this article in press as: Carelli V, et al. Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.01.023
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onset parkinsonism (DiMauro et al., 2013). A mosaic pattern of prevalent clonal expansion of deleted mtDNA seems to be a common mechanism to all these conditions (Moslemi et al., 1996), but it also occurs as a byproduct of aging (Johnston et al., 1995; Popadin et al., 2014). In 2008, there was the unexpected observation that mtDNA multiple deletions may accumulate in dominant optic atrophy “plus” syndromes associated with missense mutations affecting the GTPase domain of OPA1 gene, encoding the fusogenic protein OPA1 (Amati-Bonneau et al., 2008; Hudson et al., 2008). Thus, balancing fission and fusion is crucial to mix mtDNA genomes and favors trans-complementation, promoting the mitophagic elimination of mitochondria with excessive mutant mtDNA, but also modulating the possible clonal expansion of mutant mtDNA under specific pathological conditions. The role of fusion in mtDNA maintenance has been elegantly established in a mouse model of impaired fusion with conditional deletion of the mitofusins MFN1 and MFN2 in skeletal muscle (Chen et al., 2010). Both mtDNA depletion and accumulation of mtDNA mutation resulted from impaired fusion, remarking the need of mitochondrial fusion for mtDNA maintenance. Further evidence recently came from pathologies where MFN2 mutations may lead to accumulation of mtDNA multiple deletions in skeletal muscle, similar to OPA1 mutations, or even to mtDNA depletion (Rouzier et al., 2012; Renaldo et al., 2012; Vielhaber et al., 2013). The importance of mitochondrial dynamics in segregating and complementing mtDNA mutations has been studied in vitro, mostly using the transmitochondrial cytoplasmic hybrid (cybrid) model (King and Attardi, 1989). Complementation of different mtDNA mutations was approached by fusing respiratory-deficient cybrids, homoplasmic for each of the pathogenic mutation, and assessing respiration recovery in the heteroplasmic double mutant cybrids. The Attardi’s group failed to observe relevant complementation in the 143B.TK− derived cybrids containing both the tRNALys A8344G mutation associated with myoclonic epilepsy and ragged red fiber (MERRF) syndrome and a frameshift mutation in the ND4 subunit gene of NADH dehydrogenase (Yoneda et al., 1994; Enríquez et al., 2000). Different results were obtained by the Hayashi’s laboratory with HeLa cells-derived cybrids, showing trans-complementation between different respiration-deficient mitochondria carrying respectively a 5.196-base pair mtDNA deletion, causing Kearns-Sayre syndrome, and a mutant tRNAIle mtDNA, causing fatal cardiomyopathy (Takai et al., 1999). Further experiments mixing pathogenic mutations in mitochondrial tRNAIle and tRNALeu(UUR) genes confirmed the occurrence of trans-complementation with restored respiratory function in heteroplasmic cybrids containing both mutations (Ono et al., 2001). The contradictory results obtained by the two laboratories may depend on the different nuclear genetic background that may indeed contain diverse activated oncogenes; however, the complementation of wild type over mutant mtDNA has been highlighted by both laboratories (Attardi et al., 2002). Confirmation in cybrids that complementation between different pathogenic mutations occurs was also reached by others (D’Aurelio et al., 2004). A different experiment has been carried out by mixing into the same cybrids two non-overlapping mtDNA deletions, which complemented functionally restoring protein synthesis of mtDNA encoded subunits, but failed to mix mutant genomes among nucleoids (Gilkerson et al., 2008). This result provided a molecular mechanism to explain inheritance of mtDNA. Nucleoid structure has been long debated, with an estimation of about 2–10 mtDNA molecules coated by unspecified number of proteins (Legros et al., 2004; Iborra et al., 2004). Recently, by high-resolution microscopy the structure of nucleoids has been better clarified as single mtDNA circular molecules compacted by Tfam (Kukat et al., 2011), which forces DNA to undergo a U-turn, thus collapsing the circular mtDNA molecule (Ngo et al., 2011; Rubio-Cosials et al., 2011). This breakthrough discovery is in agreement with the failure to mix mtDNA
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genomes among nucleoids (Gilkerson et al., 2008) and changes remarkably the previous hypothesis on mtDNA transmission and segregation, including the mechanisms underlying clonal expansion of mutant mtDNA (Busch et al., 2014). Relevantly, endoplasmic reticulum-associated mitochondrial fission in yeast is linked with distribution of mitochondria and mtDNA (Murley et al., 2013). This study shows how mitochondrial division is spatially linked to nucleoids, which segregate prior to division, resulting in their distribution into newly generated tips in the mitochondrial network. Clonal expansion of mtDNA mutations has been particularly investigated for single or multiple deletions in skeletal muscle from patient’s biopsies, and these studies clearly showed that COX deficiency is limited to specific domains of the muscle fiber, closely associated with the distribution of deleted mtDNAs (Elson et al., 2002; Campbell et al., 2014). Thus, again nucleoid distribution and consequently mutant mtDNA are strictly dependent on fission and fusion of mitochondria, which in turn are strictly associated with mitophagy of isolated dysfunctional mitochondria and compensatory mitochondrial biogenesis.
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5. Concluding remarks: master regulators in balancing mitochondrial biogenesis and mitophagy
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Ultimately, very little is known about the upstream master regulators of both lysosomal function and mitochondrial biogenesis and mass homeostasis, different arms of the same homeostatic program. However, some examples start to come into play. Recently, this role was unpredictably assigned to the clock gene Rev-erb␣, whose deficiency led to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy (Woldt et al., 2013). Also Parkin can co-regulate both mitochondrial biogenesis through ubiquitination of the PGC1␣ repressor PARIS, and mitophagy by working downstream Pink1 in sensing depolarized mitochondria (Shin et al., 2011). Many others such co-regulators are coming into play and these pathways may become therapeutic targets and manipulation of mitochondrial dynamics may become crucial to interfere with the process of clonal expansion of mtDNA mutations. Initial support to this scenario has been provided by experiments in heteroplasmic cybrids overexpressing Parkin, where selection against mtDNA mutation was promoted (Suen et al., 2010). On the contrary, inhibition of fission in heteroplasmic cybrids favored the mutant over wild-type mtDNA (Malena et al., 2009). In conclusion, we are facing exciting times when all riddles of mitochondrial biology come to deep understanding, casting hope for curing mitochondrial diseases. To this end, studying segregation of mutant mtDNA in induced pluripotent stem cells (iPSCs) and in terminally differentiated tissues will be crucial (Hamalainen et al., 2013), as well as avoiding mtDNA mutations in iPSCs for their therapeutic use (Bukowiecki et al., 2014).
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Acknowledgements This work was supported by grants from MEET (ST), Futuro in Q4 Ricerca—FIRB 2013 (CZ), PRIN 2012–2015 (MR), Telethon Grants, #GGP06233, #GPP10005 and # GGP11182, the Emilia-Romagna regional program ER-MITO, and the Fondazione Galletti and a donation by the Ravaglia family (to V.C.).
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Valerio Carellia,b,∗ , Alessandra Marescaa,b , Leonardo Caporalia,b , Selena Trifunovc,b , Claudia Zannaa,c , Michela Rugoloc a
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy c Unit of Cellular Biochemistry, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy b
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Article history: Received 7 November 2014 Received in revised form 20 January 2015 Accepted 29 January 2015 Available online xxx
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Keywords: Mitochondrial DNA Mitochondrial DNA mutations Clonal expansion Mitophagy Nucleoids
Mitochondria are cytoplasmic organelles containing their own multi-copy genome. They are organized in a highly dynamic network, resulting from balance between fission and fusion, which maintains homeostasis of mitochondrial mass through mitochondrial biogenesis and mitophagy. Mitochondrial DNA (mtDNA) mutates much faster than nuclear DNA. In particular, mtDNA point mutations and deletions may occur somatically and accumulate with aging, coexisting with the wild type, a condition known as heteroplasmy. Under specific circumstances, clonal expansion of mutant mtDNA may occur within single cells, causing a wide range of severe human diseases when mutant overcomes wild type. Furthermore, mtDNA deletions accumulate and clonally expand as a consequence of deleterious mutations in nuclear genes involved in mtDNA replication and maintenance, as well as in mitochondrial fusion genes (mitofusin-2 and OPA1), possibly implicating mtDNA nucleoids segregation. We here discuss how the intricacies of mitochondrial homeostasis impinge on the intracellular propagation of mutant mtDNA. This article is part of a Directed Issue entitled: Mitochondrial Diseases. © 2015 Published by Elsevier Ltd. 25 26
Mitochondria facts: • Mitochondria form a highly dynamic network resulting from continuous fission and fusion events. • Homeostasis of mitochondrial mass is maintained by a balance between mitochondrial biogenesis and removal of damaged organelles by mitophagy. • Mitochondria are endowed of a multi-copy genome, the mtDNA, exhibiting a high mutation rate. • MtDNA mutations and deletions are associated with a wide range of human diseases. • Clonal expansion of mutant mtDNA occurs under different conditions and during aging in single cells. • Proteins involved in mitochondrial fusion are crucial for mtDNA maintenance.
夽 This article is part of a Directed Issue entitled: Mitochondrial Diseases. ∗ Corresponding author at: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Via Altura 3, 40139 Bologna, Italy. Tel.: +39 051 4966747; fax: +39 051 4966208. E-mail address: [email protected] (V. Carelli).
1. Introduction Biology of mitochondria and their genetic content, mitochon- Q2 drial DNA (mtDNA), does not obey the Mendelian rules, and remains in many aspects poorly understood. The focus on this organelle has been exponentially growing since the first mtDNA mutations were identified as the cause of neuromuscular diseases in humans, giving birth to the field of “mitochondrial medicine” (Wallace et al., 1988; Holt et al., 1988). The segregation of these mutant mtDNAs along the maternal germline, from one generation to the other, as well as the segregation in tissues during embryonic development and over the individual’s lifespan, both remain hot topics of scientific investigation and debate. In particular, we here consider how the intricacies of mitochondrial homeostasis, including maintenance of mitochondrial dynamics (fission/fusion) and mass (biogenesis/mitophagy) (Fig. 1A), impinge on the propagation within cells of one mutant mtDNA species over the remaining genomes, a phenomenon known as “clonal expansion” of mtDNA mutations (Fig. 1B). This may occur in healthiness, but most importantly in pathology during individual’s lifespan.
http://dx.doi.org/10.1016/j.biocel.2015.01.023 1357-2725/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Carelli V, et al. Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.01.023
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3. Pathology: heteroplasmy and polyplasmy of mtDNA, purifying selection and somatic segregation
Fig. 1. Mitochondrial homeostasis and mechanisms involved in clonal expansion of mutated mtDNA molecules.
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2. Physiology: the mitochondrial life cycle Mitochondria are cytoplasmic organelles carrying their multicopy small circular mDNA, and form a dynamic network resulting from continuous fission (division) and fusion events (Chan, 2012). Balance between fission and fusion is closely related to the homeostatic adjustment of mitochondrial mass to the metabolic needs of different tissues or cells (Mishra et al., 2014). Loss of this balance closely relates to regulation of apoptosis and cell death. Thus, maintenance of mitochondrial homeostasis is determined by mitochondrial biogenesis, which provides newly synthesized organelles, as opposed to autophagic elimination of damaged mitochondria, termed mitophagy (Youle and Narendra, 2011). The latter is mostly contributed by mitochondrial fission, which isolates and signals dysfunctional mitochondria for their removal. One signaling system for mitochondrial removal is the Pink1/Parkin axis, a quality control pathway that senses loss of mitochondrial membrane potential. Thus, Pink1 stabilization on the outer membrane recruits Parkin, activating the formation of the mito-autophagosome, ultimately determining mitophagy (Narendra et al., 2010). Other pathways, such as the newly recognized small GTPase Rheb, which promotes mitophagy in response to high oxidative phosphorylation (OXPHOS) activity (Melser et al., 2013), participate in the homeostatic quality control surveillance on mitochondria (Busch et al., 2014). This counteracts the damage derived from long-term exposure to reactive oxygen species produced by the respiratory chain, a contributor of the faster mtDNA mutation rate compared with nuclear DNA (Wallace, 2013). Deletions and point mutations may occur somatically and accumulate with aging, or may affect mtDNA along the germline, thus becoming maternally inherited. The high rate of variants fixed by descent in the mitochondrial genome is highlighted by the great continent and ethnic specificity of mtDNA haplotypes (Pakendorf et al., 2005).
Given the multi-copy nature of mtDNA, mutations lead to coexistence of mtDNA molecules differing in their sequence, a condition known as heteroplasmy or, if multiple sequences coexist, polyplasmy (Wallace et al., 2013). For a long time mtDNA was considered as a collection of identical genomes of clonal origin, thus, normally mtDNA in cells and tissues was assumed to be homoplasmic (Lightowlers et al., 1997). The improvement of sequencing techniques and the widespread investigation of mtDNA in human and animal tissues brought to realize that heteroplasmy was much more frequent than initially believed, in particular considering aging of postmitotic tissues where mutations accumulate with time (Larsson, 2010; Khrapko et al., 2014). Furthermore, deep sequencing revealed that heteroplasmy is universal and is built by somatic and germline transmitted mutations present at low level (Payne et al., 2013). Maternally transmitted mtDNA mutations undergo rounds of purifying selection each generation (Stewart et al., 2008; Fan et al., 2008), through a bottleneck possibly operating along the female germline, from oogonium to primary oocyte (Jenuth et al., 1996, Wai et al., 2008), to post fertilization in the first cell divisions when mtDNA replication seems to be still dormient (Cree et al., 2008). This counteracts the tendency toward irreversible accumulation of deleterious mutations (Carlson, 2013). During embryonic development mtDNA heteroplasmic mutations segregate by genetic drift into a mosaic cellular pattern as cells divide by mitosis (Howell et al., 2000). However, tissue-specific directional drift also occurs (Jenuth et al., 1997), possibly driven by specific nuclear genes (Battersby et al., 2003). Over lifespan mtDNA mutations accumulate at slow rate in single cells of postmitotic tissues, undergoing stochastic events of clonal expansion when mutant mtDNA prevails over wild type (Elson et al., 2001). This has been first noted for mtDNA deletions in human tissues from elders (Cortopassi and Arnheim, 1990; Cortopassi et al., 1992), supporting the hypothesis that progressive accumulation of mtDNA mutations with age leads to mitochondrial dysfunction at the level of single cells in postmitotic tissues such as skeletal and cardiac muscles and brain, contributing to the aging phenotype (Linneane et al., 1989; Larsson, 2010). The “mutator mouse” model has provided strong support to this hypothesis. In this animal the proofreading activity of mitochondrial polymerase ␥ (Pol␥), the only polymerase replicating mtDNA, is affected by a mutation leaving intact the replication capacity (Trifunovic et al., 2004). This mouse accumulates mtDNA mutations since embryonic development, leading to a progeroid phenotype that recapitulates many features of aging in humans (Trifunovic et al., 2004; Edgar et al., 2009; Ahlqvist et al., 2012).
4. Clonal expansion of mutant mtDNA: mitochondrial dynamics and mtDNA nucleoids Specific circumstances may promote clonal expansion of mutant mtDNA, as in the case of HIV patients under therapy with antiretroviral drugs that interfere with the activity of Pol␥ (Payne et al., 2011). In this case, the cyclic temporary reduction of mtDNA copy number at single-cell level, followed by re-expansion of the mtDNA pool, is thought to produce sub-continuous bottleneck effects with accelerated mtDNA turnover, ultimately promoting clonal expansion of pre-existing mtDNA deletions (Payne et al., 2011). Deletions of mtDNA and variable degrees of mtDNA depletion characterize the pathogenic mechanism of deleterious mutations in POLG and many other genes, involved in mtDNA replication or nucleotide balance, which are associated with a wide range of human diseases, from infantile syndromes such as Alpers-Huttenlocher syndrome to chronic progressive external ophthalmoplegia (CPEO) and late
Please cite this article in press as: Carelli V, et al. Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.01.023
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onset parkinsonism (DiMauro et al., 2013). A mosaic pattern of prevalent clonal expansion of deleted mtDNA seems to be a common mechanism to all these conditions (Moslemi et al., 1996), but it also occurs as a byproduct of aging (Johnston et al., 1995; Popadin et al., 2014). In 2008, there was the unexpected observation that mtDNA multiple deletions may accumulate in dominant optic atrophy “plus” syndromes associated with missense mutations affecting the GTPase domain of OPA1 gene, encoding the fusogenic protein OPA1 (Amati-Bonneau et al., 2008; Hudson et al., 2008). Thus, balancing fission and fusion is crucial to mix mtDNA genomes and favors trans-complementation, promoting the mitophagic elimination of mitochondria with excessive mutant mtDNA, but also modulating the possible clonal expansion of mutant mtDNA under specific pathological conditions. The role of fusion in mtDNA maintenance has been elegantly established in a mouse model of impaired fusion with conditional deletion of the mitofusins MFN1 and MFN2 in skeletal muscle (Chen et al., 2010). Both mtDNA depletion and accumulation of mtDNA mutation resulted from impaired fusion, remarking the need of mitochondrial fusion for mtDNA maintenance. Further evidence recently came from pathologies where MFN2 mutations may lead to accumulation of mtDNA multiple deletions in skeletal muscle, similar to OPA1 mutations, or even to mtDNA depletion (Rouzier et al., 2012; Renaldo et al., 2012; Vielhaber et al., 2013). The importance of mitochondrial dynamics in segregating and complementing mtDNA mutations has been studied in vitro, mostly using the transmitochondrial cytoplasmic hybrid (cybrid) model (King and Attardi, 1989). Complementation of different mtDNA mutations was approached by fusing respiratory-deficient cybrids, homoplasmic for each of the pathogenic mutation, and assessing respiration recovery in the heteroplasmic double mutant cybrids. The Attardi’s group failed to observe relevant complementation in the 143B.TK− derived cybrids containing both the tRNALys A8344G mutation associated with myoclonic epilepsy and ragged red fiber (MERRF) syndrome and a frameshift mutation in the ND4 subunit gene of NADH dehydrogenase (Yoneda et al., 1994; Enríquez et al., 2000). Different results were obtained by the Hayashi’s laboratory with HeLa cells-derived cybrids, showing trans-complementation between different respiration-deficient mitochondria carrying respectively a 5.196-base pair mtDNA deletion, causing Kearns-Sayre syndrome, and a mutant tRNAIle mtDNA, causing fatal cardiomyopathy (Takai et al., 1999). Further experiments mixing pathogenic mutations in mitochondrial tRNAIle and tRNALeu(UUR) genes confirmed the occurrence of trans-complementation with restored respiratory function in heteroplasmic cybrids containing both mutations (Ono et al., 2001). The contradictory results obtained by the two laboratories may depend on the different nuclear genetic background that may indeed contain diverse activated oncogenes; however, the complementation of wild type over mutant mtDNA has been highlighted by both laboratories (Attardi et al., 2002). Confirmation in cybrids that complementation between different pathogenic mutations occurs was also reached by others (D’Aurelio et al., 2004). A different experiment has been carried out by mixing into the same cybrids two non-overlapping mtDNA deletions, which complemented functionally restoring protein synthesis of mtDNA encoded subunits, but failed to mix mutant genomes among nucleoids (Gilkerson et al., 2008). This result provided a molecular mechanism to explain inheritance of mtDNA. Nucleoid structure has been long debated, with an estimation of about 2–10 mtDNA molecules coated by unspecified number of proteins (Legros et al., 2004; Iborra et al., 2004). Recently, by high-resolution microscopy the structure of nucleoids has been better clarified as single mtDNA circular molecules compacted by Tfam (Kukat et al., 2011), which forces DNA to undergo a U-turn, thus collapsing the circular mtDNA molecule (Ngo et al., 2011; Rubio-Cosials et al., 2011). This breakthrough discovery is in agreement with the failure to mix mtDNA
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genomes among nucleoids (Gilkerson et al., 2008) and changes remarkably the previous hypothesis on mtDNA transmission and segregation, including the mechanisms underlying clonal expansion of mutant mtDNA (Busch et al., 2014). Relevantly, endoplasmic reticulum-associated mitochondrial fission in yeast is linked with distribution of mitochondria and mtDNA (Murley et al., 2013). This study shows how mitochondrial division is spatially linked to nucleoids, which segregate prior to division, resulting in their distribution into newly generated tips in the mitochondrial network. Clonal expansion of mtDNA mutations has been particularly investigated for single or multiple deletions in skeletal muscle from patient’s biopsies, and these studies clearly showed that COX deficiency is limited to specific domains of the muscle fiber, closely associated with the distribution of deleted mtDNAs (Elson et al., 2002; Campbell et al., 2014). Thus, again nucleoid distribution and consequently mutant mtDNA are strictly dependent on fission and fusion of mitochondria, which in turn are strictly associated with mitophagy of isolated dysfunctional mitochondria and compensatory mitochondrial biogenesis.
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5. Concluding remarks: master regulators in balancing mitochondrial biogenesis and mitophagy
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Ultimately, very little is known about the upstream master regulators of both lysosomal function and mitochondrial biogenesis and mass homeostasis, different arms of the same homeostatic program. However, some examples start to come into play. Recently, this role was unpredictably assigned to the clock gene Rev-erb␣, whose deficiency led to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy (Woldt et al., 2013). Also Parkin can co-regulate both mitochondrial biogenesis through ubiquitination of the PGC1␣ repressor PARIS, and mitophagy by working downstream Pink1 in sensing depolarized mitochondria (Shin et al., 2011). Many others such co-regulators are coming into play and these pathways may become therapeutic targets and manipulation of mitochondrial dynamics may become crucial to interfere with the process of clonal expansion of mtDNA mutations. Initial support to this scenario has been provided by experiments in heteroplasmic cybrids overexpressing Parkin, where selection against mtDNA mutation was promoted (Suen et al., 2010). On the contrary, inhibition of fission in heteroplasmic cybrids favored the mutant over wild-type mtDNA (Malena et al., 2009). In conclusion, we are facing exciting times when all riddles of mitochondrial biology come to deep understanding, casting hope for curing mitochondrial diseases. To this end, studying segregation of mutant mtDNA in induced pluripotent stem cells (iPSCs) and in terminally differentiated tissues will be crucial (Hamalainen et al., 2013), as well as avoiding mtDNA mutations in iPSCs for their therapeutic use (Bukowiecki et al., 2014).
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Acknowledgements This work was supported by grants from MEET (ST), Futuro in Q4 Ricerca—FIRB 2013 (CZ), PRIN 2012–2015 (MR), Telethon Grants, #GGP06233, #GPP10005 and # GGP11182, the Emilia-Romagna regional program ER-MITO, and the Fondazione Galletti and a donation by the Ravaglia family (to V.C.).
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