CELL CYCLE 2016, VOL. 15, NO. 14, 1805–1806 http://dx.doi.org/10.1080/15384101.2016.1181876
EDITORIALS: CELL CYCLE FEATURES
Mitochondrial autophagy promotes healthy aging Anjumara Shaika,b, Alfonso Schiavib, and Natascia Venturaa,b a Institute for Clinical Chemistry and Laboratory Diagnostic, Medical Faculty of the Heinrich Heine University, D€ usseldorf, Germany; bIUF-Leibniz Research Institute for Environmental Medicine, D€usseldorf, Germany
ARTICLE HISTORY Received 5 April 2016; Accepted 19 April 2016 KEYWORDS aging; autophagy; C. elegans; cancer; frataxin; iron; mitochondria; mitophagy
Severe mitochondrial dysfunction leads to a plethora of diseases ranging from neurodegenerative disorders to cancer and accelerates the aging process. However, interestingly, in the past 10 years partial reduction of mitochondrial function has been shown to promote healthy aging from yeast to mammals. By exploiting the genetic tractable model organism Caenorhabditis elegans as a powerful tool for aging studies we have shown that this pro-longevity effect is mediated by the activation of autophagy,1 a non-selective form of cytoplasmic components recycling, which is of fundamental importance for cellular adaptation to physiological metabolic changes and in response to different types of stressors.2 Autophagy can also function as a cellular housekeeper by selectively degrading damaged or dysfunctional organelles. Mitophagy is a dedicated form of autophagy that selectively removes damaged or old mitochondria, which has been identified from yeast to mammals as an important mitochondrial quality control pathway.3 Of note, we recently reported for the first time that in C. elegans partial suppression of mitochondrial electron transport chain regulatory proteins (e.g. frataxin) extends lifespan through the activation of a pdr-1/ Parkin-, pink-1/ Pink-, and dct-1/ Bnip3-dependent mitophagy, which is promoted by the induction of a moderate iron starvation response (Fig. 1) .4 Several studies have shown that mitophagy defects are implicated in a wide array of human disorders including neurodegenerative diseases, myopathies and cancer.3 Tumor development can result from alteration of basic cellular functions such as metabolism, differentiation, proliferation and death programs. In recent years, it has been accepted that autophagy, in addition to its cell survival function, can elicit cell growth inhibition and cell death functions thus playing a Janus faced role in promoting tumor cell survival or tumor regression respectively.2 Indeed, it was originally shown that the expression of beclin-1, a central player of autophagy, has tumor suppression property and a decrease in autophagy induction contributes to the development or progression of breast cancer and other human malignancies.2 Moreover, depending on the cellular context and
tumor stage, transient activation of autophagy can either promote or suppress tumor development and progression, while prolonged activation of autophagy can eventually induce senescence, by degrading the components essential for cell survival, resulting in autophagic death.2 Interestingly, in more recent years, various strategies that can specifically trigger mitophagy in cancerous cells have been developed in an attempt to suppress malignancies, although this field is still largely unexplored. For example, linamarase/linamarin/glucose oxidase system releases glucose, acetone, and cyanide as result of lis/lin/GO enzymatic reaction; cyanide inhibits cytochrome c oxidase of the mitochondrial respiratory chain, thus triggering the activation of mitophagy, which in turn induces cell death and growth inhibition of human cancer cell lines both in vivo and in vitro.5 In another study, Nexrutine, an herbal extract derived from the bark of Phellodendron amurense that has been largely used as a dietary supplement in China and America, was shown to reduce the proliferation rate of different cancer cell lines by inducing mitochondrial damage and consequently mitophagy activation associated with an elevation of p21/p27, both important cell cycle inhibitors.6 Consistent with mitophagy as a possible tumor suppressor mechanism, reduced expression of BNIP3, a mitophagy specific regulator, was found in different type of cancers.3 Therefore developing novel approaches to activate mitophagy may lead to new strategies to prevent tumor formation or induce tumor regression. Aging is the most important risk factor for the development of different types of cancers. We found that reduced mitochondrial electron transport chain functionality results in the activation of mitophagy via iron depletion, in turn promoting lifespan extension (Fig. 1).4 And notably, we showed that reduced expression of the mitochondrial protein frataxin, which we previously found to be overexpressed in different types of cancers, induces mitophagy in an evolutionarily conserved manner.4 In order to maintain tumor microenvironment and metastasis cancerous cells
CONTACT Natascia Ventura [email protected] Auf’m Hennekamp, 40225 D€uesseldorf, Germany. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kccy. Feature to: Schiavi A, et al. Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans. Curr Biol 2015; 25(14):1810-22; PMID: 26144971; http://dx.doi.org/10.1016/j.cub.2015.05.059 © 2016 Taylor & Francis
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effective and novel strategy for treating cancer, especially when considering the variety of possible mitochondrial targeting interventions. In the past several years our knowledge on the molecular mechanisms and regulation of mitophagy has significantly advanced. However the specific role of mitophagy in human carcinogenesis is not entirely understood, mostly because research in this field is still in its infancy. Hence, a better understanding of the cross talk between iron deprivation-induced mitophagy or other mitophagy triggers, and cancer biology (e.g. cell proliferation and apoptosis), will be crucial for the development of novel anticancer therapeutics and the promotion of healthy aging (Fig. 1).
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References Figure 1. We recently reported (yellow arrows) that in C. elegans partial suppression of mitochondrial electron transport chain regulatory proteins (e.g. frataxin) extends lifespan through the activation of a pdr-1 / Parkin-, pink-1/ Pink-, and dct1/ Bnip3-dependent mitophagy, which is promoted by the induction of a moderate iron starvation response.5 Various strategies that specifically trigger mitophagy have been developed in an attempt to suppress malignancies (red arrow). It will be interesting to understand whether iron-starvation induced mitophagy can be exploited to suppress cancer ultimately extending health span.
often experience excessive iron accumulation by reprogramming iron metabolism7 and altering mitophagy execution.3 Therefore, iron starvation induction of mitophagy, via making mitochondria work at the optimal level, might be an
[1] Schiavi A, et al. Exp Gerontol 2013; 48(2):191–201; PMID:23247094; http://dx.doi.org/10.1016/j.exger.2012.12.002 [2] Kimmelman AC. Genes Dev 2011; 25(19):1999–2010; PMID:21979913; http://dx.doi.org/10.1101/gad.17558811 [3] Hamacher-Brady A, et al. Cell Mol Life Sci 2016; 73(4):775–95; PMID:26611876; http://dx.doi.org/10.1007/s00018-015-2087-8 [4] Schiavi A, et al. Curr Biol 2015; 25(14):1810–1822; PMID:26144971; http://dx.doi.org/10.1016/j.cub.2015.05.059 [5] Gargini RV, et al. Autophagy 2011; 7(5):466–76; PMID:21270513 [6] Wu X, et al. Cell Physiol Biochem 2015; 36(2):763–72; PMID:26021264; http://dx.doi.org/10.1159/000430136 [7] Torti SV, et al. Nat Rev Cancer 2013; 13(5):342–55; PMID:23594855; http://dx.doi.org/10.1038/nrc3495
EDITORIALS: CELL CYCLE FEATURES
Mitochondrial autophagy promotes healthy aging Anjumara Shaika,b, Alfonso Schiavib, and Natascia Venturaa,b a Institute for Clinical Chemistry and Laboratory Diagnostic, Medical Faculty of the Heinrich Heine University, D€ usseldorf, Germany; bIUF-Leibniz Research Institute for Environmental Medicine, D€usseldorf, Germany
ARTICLE HISTORY Received 5 April 2016; Accepted 19 April 2016 KEYWORDS aging; autophagy; C. elegans; cancer; frataxin; iron; mitochondria; mitophagy
Severe mitochondrial dysfunction leads to a plethora of diseases ranging from neurodegenerative disorders to cancer and accelerates the aging process. However, interestingly, in the past 10 years partial reduction of mitochondrial function has been shown to promote healthy aging from yeast to mammals. By exploiting the genetic tractable model organism Caenorhabditis elegans as a powerful tool for aging studies we have shown that this pro-longevity effect is mediated by the activation of autophagy,1 a non-selective form of cytoplasmic components recycling, which is of fundamental importance for cellular adaptation to physiological metabolic changes and in response to different types of stressors.2 Autophagy can also function as a cellular housekeeper by selectively degrading damaged or dysfunctional organelles. Mitophagy is a dedicated form of autophagy that selectively removes damaged or old mitochondria, which has been identified from yeast to mammals as an important mitochondrial quality control pathway.3 Of note, we recently reported for the first time that in C. elegans partial suppression of mitochondrial electron transport chain regulatory proteins (e.g. frataxin) extends lifespan through the activation of a pdr-1/ Parkin-, pink-1/ Pink-, and dct-1/ Bnip3-dependent mitophagy, which is promoted by the induction of a moderate iron starvation response (Fig. 1) .4 Several studies have shown that mitophagy defects are implicated in a wide array of human disorders including neurodegenerative diseases, myopathies and cancer.3 Tumor development can result from alteration of basic cellular functions such as metabolism, differentiation, proliferation and death programs. In recent years, it has been accepted that autophagy, in addition to its cell survival function, can elicit cell growth inhibition and cell death functions thus playing a Janus faced role in promoting tumor cell survival or tumor regression respectively.2 Indeed, it was originally shown that the expression of beclin-1, a central player of autophagy, has tumor suppression property and a decrease in autophagy induction contributes to the development or progression of breast cancer and other human malignancies.2 Moreover, depending on the cellular context and
tumor stage, transient activation of autophagy can either promote or suppress tumor development and progression, while prolonged activation of autophagy can eventually induce senescence, by degrading the components essential for cell survival, resulting in autophagic death.2 Interestingly, in more recent years, various strategies that can specifically trigger mitophagy in cancerous cells have been developed in an attempt to suppress malignancies, although this field is still largely unexplored. For example, linamarase/linamarin/glucose oxidase system releases glucose, acetone, and cyanide as result of lis/lin/GO enzymatic reaction; cyanide inhibits cytochrome c oxidase of the mitochondrial respiratory chain, thus triggering the activation of mitophagy, which in turn induces cell death and growth inhibition of human cancer cell lines both in vivo and in vitro.5 In another study, Nexrutine, an herbal extract derived from the bark of Phellodendron amurense that has been largely used as a dietary supplement in China and America, was shown to reduce the proliferation rate of different cancer cell lines by inducing mitochondrial damage and consequently mitophagy activation associated with an elevation of p21/p27, both important cell cycle inhibitors.6 Consistent with mitophagy as a possible tumor suppressor mechanism, reduced expression of BNIP3, a mitophagy specific regulator, was found in different type of cancers.3 Therefore developing novel approaches to activate mitophagy may lead to new strategies to prevent tumor formation or induce tumor regression. Aging is the most important risk factor for the development of different types of cancers. We found that reduced mitochondrial electron transport chain functionality results in the activation of mitophagy via iron depletion, in turn promoting lifespan extension (Fig. 1).4 And notably, we showed that reduced expression of the mitochondrial protein frataxin, which we previously found to be overexpressed in different types of cancers, induces mitophagy in an evolutionarily conserved manner.4 In order to maintain tumor microenvironment and metastasis cancerous cells
CONTACT Natascia Ventura [email protected] Auf’m Hennekamp, 40225 D€uesseldorf, Germany. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kccy. Feature to: Schiavi A, et al. Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans. Curr Biol 2015; 25(14):1810-22; PMID: 26144971; http://dx.doi.org/10.1016/j.cub.2015.05.059 © 2016 Taylor & Francis
1806
A. SHAIK ET AL.
effective and novel strategy for treating cancer, especially when considering the variety of possible mitochondrial targeting interventions. In the past several years our knowledge on the molecular mechanisms and regulation of mitophagy has significantly advanced. However the specific role of mitophagy in human carcinogenesis is not entirely understood, mostly because research in this field is still in its infancy. Hence, a better understanding of the cross talk between iron deprivation-induced mitophagy or other mitophagy triggers, and cancer biology (e.g. cell proliferation and apoptosis), will be crucial for the development of novel anticancer therapeutics and the promotion of healthy aging (Fig. 1).
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References Figure 1. We recently reported (yellow arrows) that in C. elegans partial suppression of mitochondrial electron transport chain regulatory proteins (e.g. frataxin) extends lifespan through the activation of a pdr-1 / Parkin-, pink-1/ Pink-, and dct1/ Bnip3-dependent mitophagy, which is promoted by the induction of a moderate iron starvation response.5 Various strategies that specifically trigger mitophagy have been developed in an attempt to suppress malignancies (red arrow). It will be interesting to understand whether iron-starvation induced mitophagy can be exploited to suppress cancer ultimately extending health span.
often experience excessive iron accumulation by reprogramming iron metabolism7 and altering mitophagy execution.3 Therefore, iron starvation induction of mitophagy, via making mitochondria work at the optimal level, might be an
[1] Schiavi A, et al. Exp Gerontol 2013; 48(2):191–201; PMID:23247094; http://dx.doi.org/10.1016/j.exger.2012.12.002 [2] Kimmelman AC. Genes Dev 2011; 25(19):1999–2010; PMID:21979913; http://dx.doi.org/10.1101/gad.17558811 [3] Hamacher-Brady A, et al. Cell Mol Life Sci 2016; 73(4):775–95; PMID:26611876; http://dx.doi.org/10.1007/s00018-015-2087-8 [4] Schiavi A, et al. Curr Biol 2015; 25(14):1810–1822; PMID:26144971; http://dx.doi.org/10.1016/j.cub.2015.05.059 [5] Gargini RV, et al. Autophagy 2011; 7(5):466–76; PMID:21270513 [6] Wu X, et al. Cell Physiol Biochem 2015; 36(2):763–72; PMID:26021264; http://dx.doi.org/10.1159/000430136 [7] Torti SV, et al. Nat Rev Cancer 2013; 13(5):342–55; PMID:23594855; http://dx.doi.org/10.1038/nrc3495
