YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation

Stibůrek, Lukáš; Cesnekova, Jana; Kostková, Olga; Fornůsková, Daniela; Vinsova, Kamila; Wenchich, László; Houštěk, J; Zeman, Jiřı́

doi:10.1091/mbc.e11-08-0674

Cited by 147 publications

(179 citation statements)

References 56 publications

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“…Mitochondrial i-AAA protease Yme1L locates at mitochondrial inner membrane and regulates quality control of mitochondrial proteins. [19][20][21][22] To clarify how Mic60/Mitofilin is degraded in mitochondria, we check the relationship between Yme1L and Mic60/Mitofilin. As WT Yme1L interacts and reacts with its substrates transiently, we mutated the glutamate residue of HEXXH motif, which is required for proteolysis in human Yme1L to glutamine (E600Q), and the mutant Yme1L-E600Q binds to its substrates stably.…”

Section: Resultsmentioning

confidence: 99%

“…19 Yme1L exerts ATPdependent proteolytic activity, resulting in either degradation or processing of its substrates such as optic atrophy 1 (OPA1) and some subunits of oxidative phosphorylation. [20][21][22] Mitochondria are dynamic organelles whose morphology are determined by continuous fusion and fission events. 23 Mfn1, Mfn2 and OPA1 are key factors for mitochondrial fusion; 24 dynamin-related protein 1 (Drp1) is a cytosolic protein and is essential for mitochondrial fission, it is recruited by mitochondrial outer membrane protein mitochondrial fission factor (Mff), mitochondrial dynamics protein 49 kDa Abbreviations: MEF, mouse embryonic fibroblast; OPA1, optic atrophy 1; Drp1, dynamin-related protein 1; Mff, mitochondrial fission factor; MiD49/51, mitochondrial dynamics proteins of 49 kDa and 51 kDa; WT, wild type; shMic60, short hairpin-mediated RNA interference to Mic60; mtDNA mitochondrial DNA; co-IP co-immunoprecitation; MICOS mitochondrial contact site and cristae organizing system…”

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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: Resultsmentioning

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

et al. 2015

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“…We observed reduced complex I activities and consequently increased ROS levels in aged dYME1L mutant flies, which is consistent with studies on mammalian cultured cell lines. 16 Importantly, deletion of dYME1L caused an increase in mitochondrial unfolded protein stress and rendered mutant flies more susceptible to genetic and environmental stresses. Furthermore, it led to impaired locomotor activity and neural and muscular degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…13 Knocking down mitochondrial i-AAA protease in cultured cells perturbed mitochondrial morphology and sensitized cells to oxidative stress and apoptotic stimuli. [14][15][16] However, the pathophysiological consequences of i-AAA loss of function at the animal level have been largely unknown. Yet, the absence of gene redundancy makes mitochondrial i-AAA protease particularly suitable for genetic studies exploring the function of mitochondrial AAA proteases in animal models.…”

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Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

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Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics

et al. 2014

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The dynamic network of mitochondria fragments under stress allowing the segregation of damaged mitochondria and, in case of persistent damage, their selective removal by mitophagy. Mitochondrial fragmentation upon depolarisation of mitochondria is brought about by the degradation of central components of the mitochondrial fusion machinery. The OMA1 peptidase mediates the degradation of long isoforms of the dynamin-like GTPase OPA1 in the inner membrane. Here, we demonstrate that OMA1-mediated degradation of OPA1 is a general cellular stress response. OMA1 is constitutively active but displays strongly enhanced activity in response to various stress insults. We identify an amino terminal stress-sensor domain of OMA1, which is only present in homologues of higher eukaryotes and which modulates OMA1 proteolysis and activation. OMA1 activation is associated with its autocatalyic degradation, which initiates from both termini of OMA1 and results in complete OMA1 turnover. Autocatalytic proteolysis of OMA1 ensures the reversibility of the response and allows OPA1-mediated mitochondrial fusion to resume upon alleviation of stress. This differentiated stress response maintains the functional integrity of mitochondria and contributes to cell survival.

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YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation

Cited by 147 publications

References 56 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

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics

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