To maintain cellular homeostasis, cells are equipped with precise systems that trigger the appropriate stress responses. Mitochondria not only provide cellular energy but also integrate stress response signaling pathways, including those regulating cell death. Several lines of evidence suggest that the mitochondrial proteins that function in this process, such as Bcl-2 family proteins in apoptosis and phosphoglycerate mutase family member 5 (PGAM5) in necroptosis, are regulated by several kinases. It has also been suggested that the phosphorylation-dependent regulation of mitochondrial fission machinery, dynamin-related protein 1 (Drp1), facilitates appropriate cellular stress responses. However, mitochondria themselves are also damaged by various stresses. To avoid the deleterious effects exerted by damaged mitochondria, cells remove these mitochondria in a selective autophagic degradation process called mitophagy. Interestingly, several kinases, such as PTEN-induced putative kinase 1 (PINK1) in mammals and stress-responsive mitogen-activated protein (MAP) kinases in yeast, have recently been shown to be involved in mitophagy. In this paper, we focus on the phosphorylation-dependent regulation of mitochondrial proteins and discuss the roles of this regulation in the mitochondrial and cellular stress responses. 1. Introduction Mitochondria play a fundamental role in cells, serving as the “powerhouses” that produce ATP through the process of oxidative phosphorylation. In addition to supplying cellular energy, mitochondria are involved in the response to several cellular stresses, such as cell death signaling and antiviral immunity [1–3]. However, mitochondria themselves are also exposed to various stresses. For example, leakage of the high-energy electrons in the respiratory chain leads to the formation of reactive oxygen species (ROS), which can damage mitochondrial DNA (mtDNA). Mutations in mtDNA result in enzymatic abnormalities in the mitochondrial respiratory chain and further oxidative stress. This vicious cycle has been considered to be involved in a wide range of human diseases, such as metabolic, aging, and neurodegenerative diseases [4]. Thus, the quality of mitochondria must be continuously monitored and maintained by various strategies. Mitochondria are dynamic organelles that constantly fuse and divide [5]. These dynamic properties are important for the maintenance of mitochondrial functions, which ultimately contribute to cell survival. A certain degree of mitochondrial damage, including mtDNA mutations, can be rescued by mitochondrial
References
[1]
H. M. McBride, M. Neuspiel, and S. Wasiak, “Mitochondria: more than just a powerhouse,” Current Biology, vol. 16, no. 14, pp. R551–R560, 2006.
[2]
X. Wang, “The expanding role of mitochondria in apoptosis,” Genes and Development, vol. 15, no. 22, pp. 2922–2933, 2001.
[3]
A. P. West, G. S. Shadel, and S. Ghosh, “Mitochondria in innate immune responses,” Nature Reviews Immunology, vol. 11, no. 6, pp. 389–402, 2011.
[4]
D. C. Wallace, “A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine,” Annual Review of Genetics, vol. 39, pp. 359–407, 2005.
[5]
S. A. Detmer and D. C. Chan, “Functions and dysfunctions of mitochondrial dynamics,” Nature Reviews Molecular Cell Biology, vol. 8, no. 11, pp. 870–879, 2007.
[6]
P. Vandenabeele, L. Galluzzi, T. Vanden Berghe, and G. Kroemer, “Molecular mechanisms of necroptosis: an ordered cellular explosion,” Nature Reviews Molecular Cell Biology, vol. 11, no. 10, pp. 700–714, 2010.
[7]
D. J. Pagliarini and J. E. Dixon, “Mitochondrial modulation: reversible phosphorylation takes center stage?” Trends in Biochemical Sciences, vol. 31, no. 1, pp. 26–34, 2006.
[8]
H. Chen, A. Chomyn, and D. C. Chan, “Disruption of fusion results in mitochondrial heterogeneity and dysfunction,” The Journal of Biological Chemistry, vol. 280, no. 28, pp. 26185–26192, 2005.
[9]
H. Chen, J. M. McCaffery, and D. C. Chan, “Mitochondrial fusion protects against neurodegeneration in the cerebellum,” Cell, vol. 130, no. 3, pp. 548–562, 2007.
[10]
G. Twig, A. Elorza, A. J. A. Molina et al., “Fission and selective fusion govern mitochondrial segregation and elimination by autophagy,” The EMBO Journal, vol. 27, no. 2, pp. 433–446, 2008.
[11]
H. Chen, S. A. Detmer, A. J. Ewald, E. E. Griffin, S. E. Fraser, and D. C. Chan, “Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development,” Journal of Cell Biology, vol. 160, no. 2, pp. 189–200, 2003.
[12]
N. Ishihara, M. Nomura, A. Jofuku et al., “Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice,” Nature Cell Biology, vol. 11, no. 8, pp. 958–966, 2009.
[13]
M. V. Alavi, S. Bette, S. Schimpf et al., “A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy,” Brain, vol. 130, no. 4, pp. 1029–1042, 2007.
[14]
S. Züchner, I. V. Mersiyanova, M. Muglia et al., “Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A,” Nature Genetics, vol. 36, no. 5, pp. 449–451, 2004.
[15]
C. Alexander, M. Votruba, U. E. A. Pesch et al., “OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28,” Nature Genetics, vol. 26, no. 2, pp. 211–215, 2000.
[16]
C. Delettre, G. Lenaers, J. M. Griffoin et al., “Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy,” Nature Genetics, vol. 26, no. 2, pp. 207–210, 2000.
[17]
C. R. Chang and C. Blackstone, “Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology,” The Journal of Biological Chemistry, vol. 282, no. 30, pp. 21583–21587, 2007.
[18]
G. M. Cereghetti, A. Stangherlin, O. Martins De Brito et al., “Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 41, pp. 15803–15808, 2008.
[19]
L. C. Gomes, G. D. Benedetto, and L. Scorrano, “During autophagy mitochondria elongate, are spared from degradation and sustain cell viability,” Nature Cell Biology, vol. 13, no. 5, pp. 589–598, 2011.
[20]
H. Kim, M. Scimia, D. Wilkinson et al., “Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia,” Molecular Cell, vol. 44, no. 4, pp. 532–544, 2011.
[21]
D. Tondera, S. Grandemange, A. Jourdain et al., “SlP-2 is required for stress-induced mitochondrial hyperfusion,” The EMBO Journal, vol. 28, no. 11, pp. 1589–1600, 2009.
[22]
D. L. Beene and J. D. Scott, “A-kinase anchoring proteins take shape,” Current Opinion in Cell Biology, vol. 19, no. 2, pp. 192–198, 2007.
[23]
K. Nakayama, I. J. Frew, M. Hagensen et al., “Siah2 regulates stability of prolyl-hydroxylases, controls HIF1α abundance, and modulates physiological responses to hypoxia,” Cell, vol. 117, no. 7, pp. 941–952, 2004.
[24]
T. Tatsuta and T. Langer, “Quality control of mitochondria: protection against neurodegeneration and ageing,” The EMBO Journal, vol. 27, no. 2, pp. 306–314, 2008.
[25]
N. Mizushima and M. Komatsu, “Autophagy: renovation of cells and tissues,” Cell, vol. 147, no. 4, pp. 728–741, 2011.
[26]
M. Tsukada and Y. Ohsumi, “Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae,” FEBS Letters, vol. 333, no. 1-2, pp. 169–174, 1993.
[27]
D. J. Klionsky, J. M. Cregg, W. A. Dunn et al., “A unified nomenclature for yeast autophagy-related genes,” Developmental Cell, vol. 5, no. 4, pp. 539–545, 2003.
[28]
N. Mizushima, T. Yoshimori, and Y. Ohsumi, “The role of atg proteins in autophagosome formation,” Annual Review of Cell and Developmental Biology, vol. 27, pp. 107–132, 2011.
[29]
H. Nakatogawa, K. Suzuki, Y. Kamada, and Y. Ohsumi, “Dynamics and diversity in autophagy mechanisms: lessons from yeast,” Nature Reviews Molecular Cell Biology, vol. 10, no. 7, pp. 458–467, 2009.
[30]
K. Okamoto, N. Kondo-Okamoto, and Y. Ohsumi, “Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy,” Developmental Cell, vol. 17, no. 1, pp. 87–97, 2009.
[31]
T. Kanki, K. Wang, Y. Cao, M. Baba, and D. J. Klionsky, “Atg32 is a mitochondrial protein that confers selectivity during mitophagy,” Developmental Cell, vol. 17, no. 1, pp. 98–109, 2009.
[32]
Y. Aoki, T. Kanki, Y. Hirota et al., “Phosphorylation of serine 114 on Atg32 mediates mitophagy,” Molecular Biology of the Cell, vol. 22, no. 17, pp. 3206–3217, 2011.
[33]
H. Saito, “Regulation of cross-talk in yeast MAPK signaling pathways,” Current Opinion in Microbiology, vol. 13, no. 6, pp. 677–683, 2010.
[34]
Y. Kurihara, T. Kanki, Y. Aoki et al., “Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast,” The Journal of Biological Chemistry, vol. 287, no. 5, pp. 3265–3272, 2012.
[35]
E. M. Valente, P. M. Abou-Sleiman, V. Caputo et al., “Hereditary early-onset Parkinson's disease caused by mutations in PINK1,” Science, vol. 304, no. 5674, pp. 1158–1160, 2004.
[36]
J. W. Pridgeon, J. A. Olzmann, L. S. Chin, and L. Li, “PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1,” PLoS Biology, vol. 5, no. 7, article e172, 2007.
[37]
H. Plun-Favreau, K. Klupsch, N. Moisoi et al., “The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1,” Nature Cell Biology, vol. 9, no. 11, pp. 1243–1252, 2007.
[38]
J. Park, S. B. Lee, S. Lee et al., “Mitochondrial dysfunction in DrosophilaPINK1 mutants is complemented by parkin,” Nature, vol. 441, no. 7097, pp. 1157–1161, 2006.
[39]
D. Narendra, A. Tanaka, D. F. Suen, and R. J. Youle, “Parkin is recruited selectively to impaired mitochondria and promotes their autophagy,” Journal of Cell Biology, vol. 183, no. 5, pp. 795–803, 2008.
[40]
D. P. Narendra, S. M. Jin, A. Tanaka et al., “PINK1 is selectively stabilized on impaired mitochondria to activate Parkin,” PLoS Biology, vol. 8, no. 1, Article ID e1000298, 2010.
[41]
N. Matsuda, S. Sato, K. Shiba et al., “PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy,” Journal of Cell Biology, vol. 189, no. 2, pp. 211–221, 2010.
[42]
S. M. Jin, M. Lazarou, C. Wang, L. A. Kane, D. P. Narendra, and R. J. Youle, “Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL,” Journal of Cell Biology, vol. 191, no. 5, pp. 933–942, 2010.
[43]
R. J. Youle and D. P. Narendra, “Mechanisms of mitophagy,” Nature Reviews Molecular Cell Biology, vol. 12, no. 1, pp. 9–14, 2011.
[44]
S. R. Yoshii, C. Kishi, N. Ishihara, and N. Mizushima, “Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane,” The Journal of Biological Chemistry, vol. 286, no. 22, pp. 19630–19640, 2011.
[45]
N. C. Chan, A. M. Salazar, A. H. Pham et al., “Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy,” Human Molecular Genetics, vol. 20, no. 9, pp. 1726–1737, 2011.
[46]
X. Wang, D. Winter, G. Ashrafi et al., “PINK1 and Parkin target miro for phosphorylation and degradation to arrest mitochondrial motility,” Cell, vol. 147, no. 4, pp. 893–906, 2011.
[47]
H. Chen and D. C. Chan, “Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases,” Human Molecular Genetics, vol. 18, no. 2, pp. R169–R176, 2009.
[48]
Z.-H. Sheng and Q. Cai, “Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration,” Nature Reviews Neuroscience, vol. 13, no. 2, pp. 77–93, 2012.
[49]
S. J. Riedl and Y. Shi, “Molecular mechanisms of caspase regulation during apoptosis,” Nature Reviews Molecular Cell Biology, vol. 5, no. 11, pp. 897–907, 2004.
[50]
R. J. Youle and A. Strasser, “The BCL-2 protein family: opposing activities that mediate cell death,” Nature Reviews Molecular Cell Biology, vol. 9, no. 1, pp. 47–59, 2008.
[51]
E. Yang, J. Zha, J. Jockel, L. H. Boise, C. B. Thompson, and S. J. Korsmeyer, “Bad, a heterodimeric partner for Bcl-x(L), and Bcl-2, displaces Bax and promotes cell death,” Cell, vol. 80, no. 2, pp. 285–291, 1995.
[52]
J. Zha, H. Harada, E. Yang, J. Jockel, and S. J. Korsmeyer, “Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L),” Cell, vol. 87, no. 4, pp. 619–628, 1996.
[53]
S. R. Datta, A. Katsov, L. Hu et al., “14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation,” Molecular Cell, vol. 6, no. 1, pp. 41–51, 2000.
[54]
A. Bonni, A. Brunet, A. E. West, S. R. Datta, M. A. Takasu, and M. E. Greenberg, “Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms,” Science, vol. 286, no. 5443, pp. 1358–1362, 1999.
[55]
H. Harada, B. Becknell, M. Wilm et al., “Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A,” Molecular Cell, vol. 3, no. 4, pp. 413–422, 1999.
[56]
A. Schürmann, A. F. Mooney, L. C. Sanders et al., “p21-Activated kinase 1 phosphorylates the death agonist Bad and protects cells from apoptosis,” Molecular and Cellular Biology, vol. 20, no. 2, pp. 453–461, 2000.
[57]
S. Cotteret, Z. M. Jaffer, A. Beeser, and J. Chernoff, “p21-activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD,” Molecular and Cellular Biology, vol. 23, no. 16, pp. 5526–5539, 2003.
[58]
T. L. T. Aho, J. Sandholm, K. J. Peltola, H. P. Mankonen, M. Lilly, and P. J. Koskinen, “Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site,” FEBS Letters, vol. 571, no. 1–3, pp. 43–49, 2004.
[59]
S. R. Datta, H. Dudek, T. Xu et al., “Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery,” Cell, vol. 91, no. 2, pp. 231–241, 1997.
[60]
H. Harada, J. S. Andersen, M. Mann, N. Terada, and S. J. Korsmeyer, “p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 17, pp. 9666–9670, 2001.
[61]
S. R. Datta, A. M. Ranger, M. Z. Lin et al., “Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis,” Developmental Cell, vol. 3, no. 5, pp. 631–643, 2002.
[62]
N. Donovan, E. B. E. Becker, Y. Konishi, and A. Bonni, “JNK phosphorylation and activation of bad couples the stress-activated signaling pathway to the cell death machinery,” The Journal of Biological Chemistry, vol. 277, no. 43, pp. 40944–40949, 2002.
[63]
Y. Konishi, M. Lehtinen, N. Donovan, and A. Bonni, “Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery,” Molecular Cell, vol. 9, no. 5, pp. 1005–1016, 2002.
[64]
J. Sunayama, F. Tsuruta, N. Masuyama, and Y. Gotoh, “JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3,” Journal of Cell Biology, vol. 170, no. 2, pp. 295–304, 2005.
[65]
J. C. Reed, “Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD,” Science, vol. 284, no. 5412, pp. 339–343, 1999.
[66]
S. Haldar, N. Jena, and C. M. Croce, “Inactivation of Bcl-2 by phosphorylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 10, pp. 4507–4511, 1995.
[67]
K. Yamamoto, H. Ichijo, and S. J. Korsmeyer, “BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M,” Molecular and Cellular Biology, vol. 19, no. 12, pp. 8469–8478, 1999.
[68]
T. Ito, X. Deng, B. Carr, and W. S. May, “Bcl-2 phosphorylation required for anti-apoptosis function,” The Journal of Biological Chemistry, vol. 272, no. 18, pp. 11671–11673, 1997.
[69]
K. Takeda, Y. Komuro, T. Hayakawa et al., “Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 30, pp. 12301–12305, 2009.
[70]
M. J. Jedrzejas, “Structure, function, and evolution of phosphoglycerate mutases: comparison with fructose-2,6-bisphosphatase, acid phosphatase, and alkaline phosphatase,” Progress in Biophysics and Molecular Biology, vol. 73, no. 2–4, pp. 263–287, 2000.
[71]
S. C. Lo and M. Hannink, “PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria,” Experimental Cell Research, vol. 314, no. 8, pp. 1789–1803, 2008.
[72]
S. C. Lo and M. Hannink, “PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex,” The Journal of Biological Chemistry, vol. 281, no. 49, pp. 37893–37903, 2006.
[73]
Y. Imai, T. Kanao, T. Sawada et al., “The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila,” PLoS Genetics, vol. 6, no. 12, Article ID e1001229, 2010.
[74]
Y. Cho, S. Challa, D. Moquin et al., “Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation,” Cell, vol. 137, no. 6, pp. 1112–1123, 2009.
[75]
S. He, L. Wang, L. Miao et al., “Receptor interacting protein Kinase-3 determines cellular necrotic response to TNF-α,” Cell, vol. 137, no. 6, pp. 1100–1111, 2009.
[76]
D. W. Zhang, J. Shao, J. Lin et al., “RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis,” Science, vol. 325, no. 5938, pp. 332–336, 2009.
[77]
Z. Wang, H. Jiang, S. Chen, F. Du, and X. Wang, “The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways,” Cell, vol. 148, no. 1-2, pp. 228–243, 2012.
[78]
P. W. Hammond, J. Alpin, C. E. Rise, M. Wright, and B. L. Kreider, “In Vitro selection and characterization of Bcl-XL-binding proteins from a mix of tissue-specific mRNA display libraries,” The Journal of Biological Chemistry, vol. 276, no. 24, pp. 20898–20906, 2001.
[79]
S. K. Niture and A. K. Jaiswal, “Inhibitor of Nrf2 (INrf2 or Keap1) protein degrades Bcl-xL via phosphoglycerate mutase 5 and controls cellular apoptosis,” The Journal of Biological Chemistry, vol. 286, no. 52, pp. 44542–44556, 2011.
[80]
Y. Ishida, Y. Sekine, H. Oguchi et al., “Prevention of apoptosis by mitochondrial phosphatase PGAM5 in the mushroom body is crucial for heat shock resistance in Drosophila melanogaster,” PLoS ONE, vol. 7, no. 2, Article ID e30265, 2012.
