Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

Sekine, Shiori; Wang, Chunxin; Sideris, Dionisia P.; Bunker, Eric; Zhang, Zhe; Youle, Richard J.

doi:10.1016/j.molcel.2019.01.002

Cited by 123 publications

(166 citation statements)

References 56 publications

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“…Subsequent actin cloud disassembly might then allow OMA-1 to mediate IMM rearrangement. While OPA1 is likely to be the relevant OMA-1 substrate in these rearrangements, other OMA-1 substrates have been identified as well, including PINK1 (Sekine et al, 2019); C11orf83 (Desmurs et al, 2015) and even OMA-1 itself (Zhang et al, 2014). Reciprocal communication from and to the mitochondrial matrix, through actin polymerization, could serve as another form of interaction between the mitochondrion and its cellular environment.…”

Section: Discussionmentioning

confidence: 99%

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Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Fung

Higgs

et al. 2019

Preprint

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statement: Mitochondrial depolarization induces Arp2/3 complex-dependent actin clouds that restrain mitochondrial shape changes induced by Oma1 on the inner mitochondrial membrane. A distinct actin network stimulates mitochondrial fission in response to calcium. Fung et al Actin and Mitochondria 2 AbstractRecent studies show that mitochondria and actin filaments work together in two contexts: 1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission, and 2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclear whether these two processes utilize similar actin assembly mechanisms. Here, we show that these are distinct actin assembly mechanisms in the acute phase after treatment (<10 min). Calcium-induced actin assembly is INF2-dependent and Arp2/3 complex-independent, whereas depolarization-induced actin assembly is Arp2/3 complexdependent and INF2-independent. The two types of actin polymerization are morphologically distinct, with calcium-induced filaments throughout the cytosol and depolarization-induced filaments as "clouds" around depolarized mitochondria. We have previously shown that calciuminduced actin stimulates increases in both mitochondrial calcium and recruitment of the dynamin GTPase Drp1. In contrast, depolarization-induced actin is temporally-associated with extensive mitochondrial dynamics that do not result in mitochondrial fission, but in circularization of the inner mitochondrial membrane (IMM). These dynamics are dependent upon the protease Oma1 and independent of Drp1. Actin cloud inhibition causes increased IMM circularization, suggesting that actin clouds limit these dynamics. Fung et alActin and Mitochondria

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Section: Discussionmentioning

confidence: 99%

“…We next examined the actin assembly factors required for ionomycin-and CCCP-induced actin polymerization. Past results have shown that ionomycin-induced actin polymerization requires the formin INF2 (Chakrabarti et al, 2018;Ji et al, 2015;Shao et al, 2015;Wales et al, 2016).…”

Section: Distinct Actin Polymerization Mechanisms Induced By Mitochonmentioning

confidence: 99%

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Fung

Higgs

et al. 2019

Preprint

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“…Subsequent actin cloud disassembly might then allow OMA1 to mediate IMM rearrangement. Although OPA1 is likely to be the relevant OMA1 substrate in these rearrangements, other OMA1 substrates have also been identified, including PINK1 (Sekine et al, 2019), C11orf83 (Desmurs et al, 2015) and even OMA1 itself (Zhang et al, 2014). Reciprocal communication from and to the mitochondrial matrix, through actin polymerization, could serve as another form of interaction between the mitochondrion and its cellular environment.…”

Section: Discussionmentioning

confidence: 99%

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Fung

Higgs

et al. 2019

Journal of Cell Science

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Recent studies show that mitochondria and actin filaments work together in two contexts: (1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission and (2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclear whether these two processes utilize similar actin assembly mechanisms. Here, we show that these are distinct actin assembly mechanisms in the acute phase after treatment (<10 min). Calcium-induced actin assembly is INF2 dependent and Arp2/3 complex independent, whereas depolarizationinduced actin assembly is Arp2/3 complex dependent and INF2 independent. The two types of actin polymerization are morphologically distinct, with calcium-induced filaments throughout the cytosol and depolarization-induced filaments as 'clouds' around depolarized mitochondria. We have previously shown that calcium-induced actin stimulates increases in both mitochondrial calcium and recruitment of the dynamin GTPase Drp1 (also known as DNM1L). In contrast, depolarization-induced actin is temporally associated with extensive mitochondrial dynamics that do not result in mitochondrial fission, but in circularization of the inner mitochondrial membrane (IMM). These dynamics are dependent on the protease OMA1 and independent of Drp1. Actin cloud inhibition causes increased IMM circularization, suggesting that actin clouds limit these dynamics. This article has an associated First Person interview with the first author of the paper.

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“…Generation of the HEK293 C2/C10 DKO cell line was described previously (Huang et al, 2018). HeLa PARL KO, HeLa OMA1 KO , HeLa OMA1 KO stably expressing OMA1 WT or OMA1 E328Q and matched HeLa WT cell lines were a kind from Richard Youle (NIH) and have been described previously (Sekine et al, 2019). HeLa YME1 KO and matched HeLa WT cell lines were a kind gift from Thomas Langer (Cologne) and have been described previously (Hartmann et al, 2016).…”

Section: Cell Culturementioning

confidence: 99%

Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations in vivo

Liu

Huang

Nguyen

et al. 2019

Preprint

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AbstractDominant mutations in the mitochondrial paralogs CHCHD2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson’s disease and ALS/FTD/myopathy, respectively. Disruption of mitochondrial cristae has been observed in mutant C10 patient tissues and animal models, but the mechanism for this disruption remains controversial. Additionally, C10 patient mutant knock-in (KI) mice were recently reported to activate a mitochondrial integrated stress response (mt-ISR) and develop cardiomyopathy not seen in C10 knockout (KO) mice, calling into question whether mutant C10 pathogenesis is related to C2/C10 normal function or purely toxic gain of function. Here, using the first C2/10 double knockout (DKO) mice, we report that C10 pathogenesis and the normal function of C2/10 are intimately linked. Similar to patients with C10 mutations, we found that C2/10 DKO mice (but not either single KO mice) have disrupted mitochondrial cristae, due to cleavage of the mitochondrial shaping protein L-OPA1 by the stress-induced peptidase OMA1. OMA1 was found to be activated similarly in affected tissues of mutant C10 KI mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities due to both C10 mutation and C2/C10 loss, and that OMA1, a driver of neurodegeneration in other contexts, may be a therapeutic target. Finally, C2/10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the mt-ISR in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.

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Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

Cited by 123 publications

References 56 publications

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations in vivo

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