Membrane depolarization activates the mitochondrial protease
            <scp>OMA</scp>
            1 by stimulating self‐cleavage

Zhang, Kuan; Li, Huihui; Song, Zhiyin

doi:10.1002/embr.201338240

Cited by 152 publications

(176 citation statements)

References 17 publications

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“…Western blot and co-IP were performed as we have described previously. 57 Cells were lysed in a Triton X-100-based lysis buffer (1% Triton X-100, 10% glycerol, 20 mM Tris,150 mM NaCl, pH7.4, 2 mM EDTA, protease inhibitor mixture). GST-or His-tagged proteins were expressed in E. coli BL21 and induced with 1 mM IPTG.…”

Section: Methodsmentioning

confidence: 99%

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

et al. 2015

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The MICOS complex (mitochondrial contact site and cristae organizing system) is essential for mitochondrial inner membrane organization and mitochondrial membrane contacts, however, the molecular regulation of MICOS assembly and the physiological functions of MICOS in mammals remain obscure. Here, we report that Mic60/Mitofilin has a critical role in the MICOS assembly, which determines the mitochondrial morphology and mitochondrial DNA (mtDNA) organization. The downregulation of Mic60/Mitofilin or Mic19/CHCHD3 results in instability of other MICOS components, disassembly of MICOS complex and disorganized mitochondrial cristae. We show that there exists direct interaction between Mic60/Mitofilin and Mic19/CHCHD3, which is crucial for their stabilization in mammals. Importantly, we identified that the mitochondrial i-AAA protease Yme1L regulates Mic60/Mitofilin homeostasis. Impaired MICOS assembly causes the formation of 'giant mitochondria' because of dysregulated mitochondrial fusion and fission. Also, mtDNA nucleoids are disorganized and clustered in these giant mitochondria in which mtDNA transcription is attenuated because of remarkable downregulation of some key mtDNA nucleoid-associated proteins.Together, these findings demonstrate that Mic60/Mitofilin homeostasis regulated by Yme1L is central to the MICOS assembly, which is required for maintenance of mitochondrial morphology and organization of mtDNA nucleoids. Mitochondria have a key role in oxidative phosphorylation and related cellular metabolism, in energy conversion, in programmed cell death, in cell growth and in diseases. Mitochondrial outer and inner membranes strongly differ in architecture and functions. The mitochondrial outer membrane forms a barrier to cytosol, and contains channels and the translocases of outer membrane, which is the main protein entry gate of mitochondria. 1,2 In contrast, the mitochondrial inner membrane consists of two morphologically distinct regions: the inner boundary membrane is in close proximity to the outer membrane and the cristae membranes that are large tubular invaginations. [3][4][5][6][7][8] The mitochondrial inner boundary and cristae membrane are physically separated by cristae junctions, which are narrow tubular or slot-like structure. 4,9 The mitochondrial cristae are arranged in regular arrays and are the main sites of ATP production in the mitochondria, but the molecules that are associated with the maintenance of cristae architecture still remain elusive. Recently, several groups identified a large protein complex, MICOS complex (mitochondrial contact site and cristae organizing system; previously named MINOS, MitOS, Mitofilin or Fcj1 complex ), that has a crucial role in the formation of cristae junctions, contact sites to the outer membrane, and the organization of inner membrane. [10][11][12][13][14] In yeast, MICOS consists of at least six subunits: Mic60 (Fcj1), Mic10 (Mio10/Mcs10/Mos1), Mic19 (Aim13/Mcs19), Mic26 (Mio27/Mcs29/Mos2), Mic12 (Aim5/ Msc12) and Mic27 (Aim37/Mcs27). In mammals, five s...

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Section: Methodsmentioning

confidence: 99%

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

et al. 2015

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“…The C-terminal self-cleavage of OMA1 in response to mitochondrial stress has been proposed to promote its activity (Zhang et al, 2014), whereas its complete self-degradation permits Box 2. What is the role of S-OPA1 in mitochondrial dynamics?…”

Section: Healthy Conditionsmentioning

confidence: 99%

OPA1 processing in cell death and disease – the long and short of it

MacVicar

Langer

2016

Journal of Cell Science

369

318

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The regulation of mitochondrial dynamics by the GTPase OPA1, which is located at the inner mitochondrial membrane, is crucial for adapting mitochondrial function and preserving cellular health. OPA1 governs the delicate balance between fusion and fission in the dynamic mitochondrial network. A disturbance of this balance, often observed under stress and pathologic conditions, causes mitochondrial fragmentation and can ultimately result in cell death. As discussed in this Commentary, these morphological changes are regulated by proteolytic processing of OPA1 by the inner-membrane peptidases YME1L (also known as YME1L1) and OMA1. Long, membrane-bound forms of OPA1 are required for mitochondrial fusion, but their processing to short, soluble forms limits fusion and can facilitate mitochondrial fission. Excessive OPA1 processing by the stress-activated protease OMA1 promotes mitochondrial fragmentation and, if persistent, triggers cell death and tissue degeneration in vivo. The prevention of OMA1-mediated OPA1 processing and mitochondrial fragmentation might thus offer exciting therapeutic potential for human diseases associated with mitochondrial dysfunction.

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“…Studies by our group established that Oma1 per se is also an important stress-activated protease required for cell survival (32). In mammalian cells, Oma1 mediates rapid proteolytic processing of the long membraneanchored form of OPA1 (L-OPA1), thereby promoting IM fragmentation and subsequent cellular MQC actions in response to homeostatic insults (8,19,200). Conversely, the mitochondrial network remains intact or even hyperfused in stressed Oma1-deficient mouse embryonic fibroblasts (19,152).…”

Section: Inner Membrane Subproteomementioning

confidence: 99%

Mitochondrial Protein Quality Control: The Mechanisms Guarding Mitochondrial Health

Bohovych

Chan

Khalimonchuk

2015

Antioxidants & Redox Signaling

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Significance: Mitochondria are complex dynamic organelles pivotal for cellular physiology and human health. Failure to maintain mitochondrial health leads to numerous maladies that include late-onset neurodegenerative diseases and cardiovascular disorders. Furthermore, a decline in mitochondrial health is prevalent with aging. A set of evolutionary conserved mechanisms known as mitochondrial quality control (MQC) is involved in recognition and correction of the mitochondrial proteome. Recent Advances: Here, we review current knowledge and latest developments in MQC. We particularly focus on the proteolytic aspect of MQC and its impact on health and aging. Critical Issues: While our knowledge about MQC is steadily growing, critical gaps remain in the mechanistic understanding of how MQC modules sense damage and preserve mitochondrial welfare, particularly in higher organisms. Future Directions: Delineating how coordinated action of the MQC modules orchestrates physiological responses on both organellar and cellular levels will further elucidate the current picture of MQC's role and function in health, cellular stress, and degenerative diseases. Antioxid. Redox Signal. 22, 977-994.

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Membrane depolarization activates the mitochondrial protease OMA 1 by stimulating self‐cleavage

Cited by 152 publications

References 17 publications

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

OPA1 processing in cell death and disease – the long and short of it

Mitochondrial Protein Quality Control: The Mechanisms Guarding Mitochondrial Health

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