- Email: [email protected]
PINK1 and Parkin Flag Miro to Direct Mitochondrial Traffic
for SREBP-1 activation (Okazaki et al., 2010; Xu et al., 2010). It is remarkable that the connection between SREBP and the folate cycle and homocysteine metabolism was not found sooner, given the previous microarray analysis of different transgenic and knockout mouse models in the SREBP pathway (Horton et al., 2003). Using these transgenic models, it will be interesting to investigate how SREBP-1-mediated changes in the one-carbon cycle impact other methylation-dependent processes such as DNA methylation (Blom and Smulders, 2011). Given the known link between metabolism and epigenetics,
this may open the door on another very interesting chapter in SREBP biology. REFERENCES Blom, H.J., and Smulders, Y. (2011). J. Inherit. Metab. Dis. 34, 75–81. DeBose-Boyd, R.A., Brown, M.S., Li, W.P., Nohturfft, A., Goldstein, J.L., and Espenshade, P.J. (1999). Cell 99, 703–712. Goldstein, J.L., DeBose-Boyd, R.A., and Brown, M.S. (2006). Cell 124, 35–46. Hegarty, B.D., Bobard, A., Hainault, I., Ferre´, P., Bossard, P., and Foufelle, F. (2005). Proc. Natl. Acad. Sci. USA 102, 791–796. Horton, J.D., Goldstein, J.L., and Brown, M.S. (2002). J. Clin. Invest. 109, 1125–1131.
Horton, J.D., Shah, N.A., Warrington, J.A., Anderson, N.N., Park, S.W., Brown, M.S., and Goldstein, J.L. (2003). Proc. Natl. Acad. Sci. USA 100, 12027– 12032. Li, S., Brown, M.S., and Goldstein, J.L. (2010). Proc. Natl. Acad. Sci. USA 107, 3441–3446. Okazaki, H., Goldstein, J.L., Brown, M.S., and Liang, G. (2010). J. Biol. Chem. 285, 6801–6810. Walker, A.K., Jacobs, R.L., Watts, J.L., Rottiers, V., Jiang, K., Finnegan, D.M., Shioda, T., Hansen, M., Yang, F., Niebergall, L.J., et al. (2011). Cell 147, this issue, 840–852. Xu, Y., Zhang, M., Wang, Y., Kadambi, P., Dave, V., Lu, L.J., and Whitsett, J.A. (2010). BMC Genomics 11, 451.
PINK1 and Parkin Flag Miro to Direct Mitochondrial Traffic Lesley A. Kane1 and Richard J. Youle1,* 1National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA *Correspondence: [email protected] DOI 10.1016/j.cell.2011.10.028
The Parkinson’s disease proteins PINK1 and Parkin are proposed guardians of mitochondrial fidelity, targeting damaged mitochondria for degradation by mitophagy. In this issue of Cell, Wang et al. (2011) now show that PINK1 and Parkin also regulate mitochondrial trafficking and quarantine damaged mitochondria by severing their connection to the microtubule network. To maintain the mitochondrial network in good working order, mitochondria undergo continuous cycles of fission and fusion, promoting the redistribution of refurbished contents throughout the system. Sometimes, however, mitochondria can become too badly damaged to be rescued by this cycle and must be culled from the network. We now understand that these damaged organelles can be recycled by a form of mitochondrial autophagy known as mitophagy. Two proteins known to be mutated in certain forms of early onset Parkinson’s disease, the E3 ubiquitin ligase Parkin and the serine/threonine kinase PINK1, mediate mitophagy following mitochondrial damage and target specific substrates for pro-
teasomal degradation (Deas et al., 2011; Kawajiri et al., 2011). In this issue of Cell, Wang et al. (2011) identify the mitochondrial outer-membrane protein Miro as a substrate of PINK1 and show that it is degraded through a Parkin-dependent mechanism. Destruction of Miro unhooks damaged mitochondria from the microtubule network, preventing their transport throughout the cell. Previous studies have shown that the PINK1/Parkin mitochondrial surveillance pathway is activated when degradation of PINK1 is inhibited, leading to an increase in the abundance of PINK1 on the mitochondrial outer membrane. This increase results in the recruitment of Parkin to mitochondria by a kinase-depen-
dent mechanism. Once present on mitochondria, Parkin ubiquitinates a subset of protein targets, leading to their proteasomal degradation and ultimately the destruction of the entire damaged organelle via mitophagy (Figure 1). As PINK1 and Parkin mutations are linked to neurodegeneration in Parkinson’s disease, the study by Wang et al. adds the important finding that Parkin is recruited to damaged mitochondria not only in cultured cell lines (Narendra et al., 2008), but also in primary neurons. Now, Miro has been identified as a PINK1 substrate. Miro is a Rho-like GTPase that plays an important role in the movement of mitochondria within cells. It is anchored by a single C-terminal
Cell 147, November 11, 2011 ª2011 Elsevier Inc. 721
transmembrane domain in the Because Parkin and PINK1 outer mitochondrial memwere first implicated in mibrane and has two GTPase tophagy, there have been domains and two EF hands many models to explain that face the cytosol and are precisely what their role is in critical for Miro function this process. However, there (Fransson et al., 2003; Frederis little consensus on how ick et al., 2004). The protein PINK1 recruits Parkin or how connects mitochondria to Parkin-tagged mitochondria microtubules via its binding are recognized by autophapartners Milton and kinesin gosomes. One hypothesis is heavy chain (KHC) and is that Parkin recruitment is required for mitochondrial a result of direct phosphorylatransport. Neuronal cells in tion and/or binding by PINK1. particular depend on efficient It has also been suggested trafficking of mitochondria to that these two enzymes may supply distant subcellular have shared substrates and locations between the cell that phosphorylation of these body and the axon terminal, substrates by PINK1 leads to and defects in this process the recruitment of Parkin. are associated with neuron The discovery that Miro is dysfunction (Guo et al., 2005). bound by PINK1 and Parkin The study in this issue by and is likely a substrate of Wang et al. made the initial both adds weight to the latter observation that overexpres‘‘shared substrate’’ hypothsion of PINK1 or Parkin in esis. Given the number of Parcultured mouse or fly neurons kin substrates on the mitoresults in arrest of mitochonchondrial outer membrane, it drial motion. Because the is unlikely that Miro is unique Miro/Milton/KHC complex is in this respect. The study by the most characterized pathWang et al. not only reveals way involved in mitochondrial a glimpse into how PINK1 movement and Miro and its and Parkin cooperate, but partner Milton can bind to also shows that mitochondrial PINK1 (Weihofen et al., quality control systems can 2009), the authors studied directly alter mitochondrial Figure 1. Miro in Mitochondrial Autophagy the connection between Miro transport and raises the (A) In cells with healthy mitochondria, Miro and its binding partners connect and the PINK1/Parkin pathpossibility that one aspect of mitochondria to microtubules, facilitating trafficking of the organelles to way. They found that Miro Parkinson’s disease is the various cellular locations. (B) Upon mitochondrial damage, PINK1 levels are stabilized on the outer can be directly phosphoryinappropriate trafficking of membrane, resulting in the recruitment of Parkin and modification of Miro. The lated by PINK1 and that, damaged mitochondria. inset shows the PINK1/Parkin/Miro complex described by Wang et al. upon damage to mitochon(C) Through phosphorylation, ubiquitination, and proteasomal pathways, Miro ACKNOWLEDGMENTS dria, Miro is degraded in a is degraded. The stationary damaged mitochondrion is segregated and can then undergo mitophagy. Parkin-dependent manner. This work was supported by the InThe authors also identify a tramural Research Program of the PINK1/Parkin/Miro complex (Figure 1). et al., 2011). These structures play NIH, National Institute of Neurological Disorders This suggests that Miro is a substrate multifaceted roles in the maintenance of and Stroke. and binding partner of both PINK1 and the lipid bilayers of both organelles and REFERENCES Parkin. The final outcome of the modi- are important locations for calcium fication and degradation of Miro is the release and signaling. One might spec- Deas, E., Wood, N.W., and Plun-Favreau, H. arrest and segregation of damaged ulate that, in addition to halting mito- (2011). Biochim. Biophys. Acta 1813, 623–633. mitochondria prior to their degradation chondrial traffic, Miro degradation by Fransson, A., Ruusala, A., and Aspenstro¨m, P. by mitophagy, thus protecting the healthy the PINK1/Parkin pathway may also (2003). J. Biol. Chem. 278, 6495–6502. mitochondrial network. free the ER from mitochondrial tethers. Frederick, R.L., McCaffery, J.M., Cunningham, Along with its role in mitochondrial traf- This secondary role might protect the K.W., Okamoto, K., and Shaw, J.M. (2004). ficking, Miro (and its yeast homolog ER from damaged mitochondria, and J. Cell Biol. 167, 87–98. Gem1p) has now been localized to mito- the loss of ER contacts may facilitate Guo, X., Macleod, G.T., Wellington, A., Hu, F., chondria-ER contact sites (Kornmann mitophagy. Panchumarthi, S., Schoenfield, M., Marin, L., 722 Cell 147, November 11, 2011 ª2011 Elsevier Inc.
Charlton, M.P., Atwood, H.L., and Zinsmaier, K.E. (2005). Neuron 47, 379–393.
Kornmann, B., Osman, C., and Walter, P. (2011). Proc. Natl. Acad. Sci. USA 108, 14151– 14156.
Wang, X., Winter, D., Ashrafi, G., Schlehe, J., Wong, Y.L., Selkoe, D., Rice, S., Steen, J., LaVoie, M.J., and Schwarz, T.L. (2011). Cell 147, this issue, 893–906.
Kawajiri, S., Saiki, S., Sato, S., and Hattori, N. (2011). Trends Pharmacol. Sci. 32, 573–580.
Narendra, D., Tanaka, A., Suen, D.F., and Youle, R.J. (2008). J. Cell Biol. 183, 795–803.
Weihofen, A., Thomas, K.J., Ostaszewski, B.L., Cookson, M.R., and Selkoe, D.J. (2009). Biochemistry 48, 2045–2052.
Cell 147, November 11, 2011 ª2011 Elsevier Inc. 723
this may open the door on another very interesting chapter in SREBP biology. REFERENCES Blom, H.J., and Smulders, Y. (2011). J. Inherit. Metab. Dis. 34, 75–81. DeBose-Boyd, R.A., Brown, M.S., Li, W.P., Nohturfft, A., Goldstein, J.L., and Espenshade, P.J. (1999). Cell 99, 703–712. Goldstein, J.L., DeBose-Boyd, R.A., and Brown, M.S. (2006). Cell 124, 35–46. Hegarty, B.D., Bobard, A., Hainault, I., Ferre´, P., Bossard, P., and Foufelle, F. (2005). Proc. Natl. Acad. Sci. USA 102, 791–796. Horton, J.D., Goldstein, J.L., and Brown, M.S. (2002). J. Clin. Invest. 109, 1125–1131.
Horton, J.D., Shah, N.A., Warrington, J.A., Anderson, N.N., Park, S.W., Brown, M.S., and Goldstein, J.L. (2003). Proc. Natl. Acad. Sci. USA 100, 12027– 12032. Li, S., Brown, M.S., and Goldstein, J.L. (2010). Proc. Natl. Acad. Sci. USA 107, 3441–3446. Okazaki, H., Goldstein, J.L., Brown, M.S., and Liang, G. (2010). J. Biol. Chem. 285, 6801–6810. Walker, A.K., Jacobs, R.L., Watts, J.L., Rottiers, V., Jiang, K., Finnegan, D.M., Shioda, T., Hansen, M., Yang, F., Niebergall, L.J., et al. (2011). Cell 147, this issue, 840–852. Xu, Y., Zhang, M., Wang, Y., Kadambi, P., Dave, V., Lu, L.J., and Whitsett, J.A. (2010). BMC Genomics 11, 451.
PINK1 and Parkin Flag Miro to Direct Mitochondrial Traffic Lesley A. Kane1 and Richard J. Youle1,* 1National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA *Correspondence: [email protected] DOI 10.1016/j.cell.2011.10.028
The Parkinson’s disease proteins PINK1 and Parkin are proposed guardians of mitochondrial fidelity, targeting damaged mitochondria for degradation by mitophagy. In this issue of Cell, Wang et al. (2011) now show that PINK1 and Parkin also regulate mitochondrial trafficking and quarantine damaged mitochondria by severing their connection to the microtubule network. To maintain the mitochondrial network in good working order, mitochondria undergo continuous cycles of fission and fusion, promoting the redistribution of refurbished contents throughout the system. Sometimes, however, mitochondria can become too badly damaged to be rescued by this cycle and must be culled from the network. We now understand that these damaged organelles can be recycled by a form of mitochondrial autophagy known as mitophagy. Two proteins known to be mutated in certain forms of early onset Parkinson’s disease, the E3 ubiquitin ligase Parkin and the serine/threonine kinase PINK1, mediate mitophagy following mitochondrial damage and target specific substrates for pro-
teasomal degradation (Deas et al., 2011; Kawajiri et al., 2011). In this issue of Cell, Wang et al. (2011) identify the mitochondrial outer-membrane protein Miro as a substrate of PINK1 and show that it is degraded through a Parkin-dependent mechanism. Destruction of Miro unhooks damaged mitochondria from the microtubule network, preventing their transport throughout the cell. Previous studies have shown that the PINK1/Parkin mitochondrial surveillance pathway is activated when degradation of PINK1 is inhibited, leading to an increase in the abundance of PINK1 on the mitochondrial outer membrane. This increase results in the recruitment of Parkin to mitochondria by a kinase-depen-
dent mechanism. Once present on mitochondria, Parkin ubiquitinates a subset of protein targets, leading to their proteasomal degradation and ultimately the destruction of the entire damaged organelle via mitophagy (Figure 1). As PINK1 and Parkin mutations are linked to neurodegeneration in Parkinson’s disease, the study by Wang et al. adds the important finding that Parkin is recruited to damaged mitochondria not only in cultured cell lines (Narendra et al., 2008), but also in primary neurons. Now, Miro has been identified as a PINK1 substrate. Miro is a Rho-like GTPase that plays an important role in the movement of mitochondria within cells. It is anchored by a single C-terminal
Cell 147, November 11, 2011 ª2011 Elsevier Inc. 721
transmembrane domain in the Because Parkin and PINK1 outer mitochondrial memwere first implicated in mibrane and has two GTPase tophagy, there have been domains and two EF hands many models to explain that face the cytosol and are precisely what their role is in critical for Miro function this process. However, there (Fransson et al., 2003; Frederis little consensus on how ick et al., 2004). The protein PINK1 recruits Parkin or how connects mitochondria to Parkin-tagged mitochondria microtubules via its binding are recognized by autophapartners Milton and kinesin gosomes. One hypothesis is heavy chain (KHC) and is that Parkin recruitment is required for mitochondrial a result of direct phosphorylatransport. Neuronal cells in tion and/or binding by PINK1. particular depend on efficient It has also been suggested trafficking of mitochondria to that these two enzymes may supply distant subcellular have shared substrates and locations between the cell that phosphorylation of these body and the axon terminal, substrates by PINK1 leads to and defects in this process the recruitment of Parkin. are associated with neuron The discovery that Miro is dysfunction (Guo et al., 2005). bound by PINK1 and Parkin The study in this issue by and is likely a substrate of Wang et al. made the initial both adds weight to the latter observation that overexpres‘‘shared substrate’’ hypothsion of PINK1 or Parkin in esis. Given the number of Parcultured mouse or fly neurons kin substrates on the mitoresults in arrest of mitochonchondrial outer membrane, it drial motion. Because the is unlikely that Miro is unique Miro/Milton/KHC complex is in this respect. The study by the most characterized pathWang et al. not only reveals way involved in mitochondrial a glimpse into how PINK1 movement and Miro and its and Parkin cooperate, but partner Milton can bind to also shows that mitochondrial PINK1 (Weihofen et al., quality control systems can 2009), the authors studied directly alter mitochondrial Figure 1. Miro in Mitochondrial Autophagy the connection between Miro transport and raises the (A) In cells with healthy mitochondria, Miro and its binding partners connect and the PINK1/Parkin pathpossibility that one aspect of mitochondria to microtubules, facilitating trafficking of the organelles to way. They found that Miro Parkinson’s disease is the various cellular locations. (B) Upon mitochondrial damage, PINK1 levels are stabilized on the outer can be directly phosphoryinappropriate trafficking of membrane, resulting in the recruitment of Parkin and modification of Miro. The lated by PINK1 and that, damaged mitochondria. inset shows the PINK1/Parkin/Miro complex described by Wang et al. upon damage to mitochon(C) Through phosphorylation, ubiquitination, and proteasomal pathways, Miro ACKNOWLEDGMENTS dria, Miro is degraded in a is degraded. The stationary damaged mitochondrion is segregated and can then undergo mitophagy. Parkin-dependent manner. This work was supported by the InThe authors also identify a tramural Research Program of the PINK1/Parkin/Miro complex (Figure 1). et al., 2011). These structures play NIH, National Institute of Neurological Disorders This suggests that Miro is a substrate multifaceted roles in the maintenance of and Stroke. and binding partner of both PINK1 and the lipid bilayers of both organelles and REFERENCES Parkin. The final outcome of the modi- are important locations for calcium fication and degradation of Miro is the release and signaling. One might spec- Deas, E., Wood, N.W., and Plun-Favreau, H. arrest and segregation of damaged ulate that, in addition to halting mito- (2011). Biochim. Biophys. Acta 1813, 623–633. mitochondria prior to their degradation chondrial traffic, Miro degradation by Fransson, A., Ruusala, A., and Aspenstro¨m, P. by mitophagy, thus protecting the healthy the PINK1/Parkin pathway may also (2003). J. Biol. Chem. 278, 6495–6502. mitochondrial network. free the ER from mitochondrial tethers. Frederick, R.L., McCaffery, J.M., Cunningham, Along with its role in mitochondrial traf- This secondary role might protect the K.W., Okamoto, K., and Shaw, J.M. (2004). ficking, Miro (and its yeast homolog ER from damaged mitochondria, and J. Cell Biol. 167, 87–98. Gem1p) has now been localized to mito- the loss of ER contacts may facilitate Guo, X., Macleod, G.T., Wellington, A., Hu, F., chondria-ER contact sites (Kornmann mitophagy. Panchumarthi, S., Schoenfield, M., Marin, L., 722 Cell 147, November 11, 2011 ª2011 Elsevier Inc.
Charlton, M.P., Atwood, H.L., and Zinsmaier, K.E. (2005). Neuron 47, 379–393.
Kornmann, B., Osman, C., and Walter, P. (2011). Proc. Natl. Acad. Sci. USA 108, 14151– 14156.
Wang, X., Winter, D., Ashrafi, G., Schlehe, J., Wong, Y.L., Selkoe, D., Rice, S., Steen, J., LaVoie, M.J., and Schwarz, T.L. (2011). Cell 147, this issue, 893–906.
Kawajiri, S., Saiki, S., Sato, S., and Hattori, N. (2011). Trends Pharmacol. Sci. 32, 573–580.
Narendra, D., Tanaka, A., Suen, D.F., and Youle, R.J. (2008). J. Cell Biol. 183, 795–803.
Weihofen, A., Thomas, K.J., Ostaszewski, B.L., Cookson, M.R., and Selkoe, D.J. (2009). Biochemistry 48, 2045–2052.
Cell 147, November 11, 2011 ª2011 Elsevier Inc. 723