Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics

Cherok, Edward; Xu, Shan; Li, Sunan; Das, Shweta; Meltzer, W. Alex; Zalzman, Michal; Wang, Chunxin; Karbowski, Mariusz

doi:10.1091/mbc.e16-04-0208

Cited by 78 publications

(90 citation statements)

References 76 publications

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“…The matrix protein, Hsp60, likewise did not undergo peroxisomal translocation following CCCP treatment (Fig B). It has been reported that Drp1, Fis1, Mitofusin (MFN) 1/2, MiD49, and Mcl1 interact with MITOL as substrates . We consequently also examined the subcellular localization of these proteins following CCCP treatment.…”

Section: Resultsmentioning

confidence: 99%

Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes

et al. 2019

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Ubiquitylation of outer mitochondrial membrane (OMM) proteins is closely related to the onset of familial Parkinson's disease. Typically, a reduction in the mitochondrial membrane potential results in Parkin‐mediated ubiquitylation of OMM proteins, which are then targeted for proteasomal and mitophagic degradation. The role of ubiquitylation of OMM proteins with non‐degradative fates, however, remains poorly understood. In this study, we find that the mitochondrial E3 ubiquitin ligase MITOL/March5 translocates from depolarized mitochondria to peroxisomes following mitophagy stimulation. This unusual redistribution is mediated by peroxins (peroxisomal biogenesis factors) Pex3/16 and requires the E3 ligase activity of Parkin, which ubiquitylates K268 in the MITOL C‐terminus, essential for p97/VCP‐dependent mitochondrial extraction of MITOL. These findings imply that ubiquitylation directs peroxisomal translocation of MITOL upon mitophagy stimulation and reveal a novel role for ubiquitin as a sorting signal that allows certain specialized proteins to escape from damaged mitochondria.

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Section: Resultsmentioning

confidence: 99%

Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes

et al. 2019

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“…The denaturing immunoprecipitation ( Fig. 7a) was adapted from [21]: Harvested cells were resuspended in denaturing buffer (1% SDS, 5 mM EDTA, 10 mM β-mercaptoethanol) and incubated at 100°C for 10 min. After centrifugation at 21,000 × g for 5 min to clear the lysate of insoluble debris the supernatant was diluted by addition of ten times its volume of immunoprecipitation buffer (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 0.5% NP-40, 5 mM N-ethylmaleimide, and protease inhibitors) and protein concentration was measured by Bradford analysis.…”

Section: Immunoprecipitationmentioning

confidence: 99%

MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment

et al. 2020

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Cells experiencing delays in mitotic progression are prone to undergo apoptosis unless they can exit mitosis before proapoptotic factors reach a critical threshold. Microtubule targeting agents (MTAs) arrest cells in mitosis and induce apoptotic cell death engaging the BCL2 network. Degradation of the antiapoptotic BCL2 family member MCL-1 is considered to set the time until onset of apoptosis upon MTA treatment. MCL1 degradation involves its interaction with one of its key binding partners, the proapoptotic BH3-only protein NOXA. Here, we report that the mitochondria-associated E3ligase MARCH5, best known for its role in mitochondrial quality control and regulation of components of the mitochondrial fission machinery, controls the levels of MCL1/NOXA protein complexes in steady state as well as during mitotic arrest. Inhibition of MARCH5 function sensitizes cancer cells to the proapoptotic effects of MTAs by the accumulation of NOXA and primes cancer cells that may undergo slippage to escape death in mitosis to cell death in the next G1 phase. We propose that inhibition of MARCH5 may be a suitable strategy to sensitize cancer cells to antimitotic drug treatment.

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“…Human mutations in DRP1 or DYN2 have been associated with neurological impairments (Gonzalez-Jamett et al, 2014; Vanstone et al, 2016; Waterham et al, 2007). Drp1, despite lacking a transmembrane domain, cycles from the cytosol to spots on the mitochondrial outer membrane (Smirnova et al, 1998) by interacting with several proteins, including Fis1, Mff, MiD49, MiD51 and a BAR-domain protein endophilin B1 (Cerveny et al, 2001; Cherok et al, 2017; Fekkes et al, 2000; Gandre-Babbe and van der Bliek, 2008; Otera et al, 2010; Palmer et al, 2011; Tieu and Nunnari, 2000; Zhao et al, 2011). The mitochondrial receptors are suggested to regulate Drp1-mediated fission in response to other signals (Koirala et al, 2013; Lackner et al, 2009; Loson et al, 2014; Loson et al, 2013).…”

Section: Cellular Machinery Of Mitochondrial Fissionmentioning

confidence: 99%

“…More recently, Drp1 and its mitochondrial receptors have been linked to Bcl-2 family proteins in a different manner. Deletion of either Drp1 or Mff results in increased ubiquitination and degradation of MiD49 and the anti-apoptotic Bcl-2 family protein Mcl-1, which is mediated by E3 ubiquitin ligase MARCH5 located on the the outer mitochondrial membrane (Cherok et al, 2017). Drp1 is itself posttranslationally regulated by activating phosphorylation at Ser616 and inhibitory phosphorylation at Ser637.…”

Section: Cellular Machinery Of Mitochondrial Fissionmentioning

confidence: 99%

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics

Abstract: In addition to their direct roles in mitochondrial fission, Mff and Drp1 act as regulatory factors and control mitochondrial fission and fusion through a Ub-dependent mechanism. The E3 Ub ligase MARCH5 is negatively controlled by Mff and Drp1.

Cited by 78 publications

References 76 publications

Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes

Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes

MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

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