Dynamics of nucleoid structure regulated by mitochondrial fission contributes to cristae reformation and release of cytochrome
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Ban-Ishihara, Reiko; Ishihara, Takaya; Sasaki, Narie; Mihara, Katsuyoshi; Ishihara, Naotada

doi:10.1073/pnas.1301951110

Cited by 198 publications

(218 citation statements)

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“…Recently, mitochondrial fusion and fission factors have been shown to influence the organization of mtDNA nucleoids. 41,52,53 In the present study, we found that Mic60/Mitofilin has an important role in the maintaining of mtDNA nucleoid organization and function in mammals ( Figures 5B and 6a). Thus, an important question is how Mic60/Mitofilin regulates the distribution and size of mtDNA nucleoids?…”

Section: Discussionsupporting

confidence: 61%

“…Previous study showed that Mic60/Mitofilin was contained in purified HeLa mtDNA nucleoids 49 and embedded in mitochondrial inner membrane with its C-terminus facing mitochondrial intermembrane space. 47,50 We then checked the effect of A recent study found that the deletion of Drp1 results in enlarged and clustered mitochondrial nucleoids; 41 we showed that Mic60/Mitofilin deficiency caused a remarkable reduced Drp1 ( Figure 4D). To investigate whether the clustering of mtDNA nucleoids induced by shMic60 is due to downregulation of Drp1, we overexpressed Drp1-YFP in WT or shMic60 MEFs and analyzed the morphology of mitochondria and mtDNA nucleoids.…”

Section: Downregulation Of Mic60/mitofilin Causes Giant Mitochondria mentioning

confidence: 97%

“…38,39 mtDNA nucleoids are crucial for the biogenesis and maintenance of mtDNA. 40 mtDNA nucleoids are dynamic and relatively uniform in shape and size, 41 but the factors for controlling the distribution and organization of mtDNA nucleoids remain to be explored.…”

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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: Discussionsupporting

confidence: 61%

Section: Downregulation Of Mic60/mitofilin Causes Giant Mitochondria mentioning

confidence: 97%

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

et al. 2015

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“…22 Recently, Ban-Ishihara reported that Drp1-dependent mitochondrial fission regulates cytochrome c release via mitochondrial DNA distribution and cristae reformation. 23 Presumably, mitochondrial fragmentation is determined as a balance between fission and fusion of mitochondria. Although accumulation of fission GTPase Drp1 on mitochondria during apoptosis has been reported by several studies, 21,24-26 insufficient mitochondrial fusion might also contribute to cellular apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

Sumida¹,

Doi²,

Ogasawara³

et al. 2015

Journal of the American Society of Nephrology

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Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich in mitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney-heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography, were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in the mitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI.

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“…One study showed that in a rhabdomyosarcoma carrying 75 -80% of the MELAS A3243G mutations, knockdown of the profission proteins hDrp1 or human fission factor (hFis1) resulted in increased heteroplasmy levels of the mutant allele, which might be attributed to decreased mitophagic clearance of mutant mtDNA containing mitochondrial fragments [96], although this was not formally tested. Alternatively, inhibition of fission by dynamin-related protein-1 (Drp1) knockdown might result in a higher threshold of expression of an OXPHOS phenotype as it also seems to promote nucleoid clustering and thus perhaps functional complementation [96,97], Conditional knockouts of Mfn1 and 2 in mouse skeletal muscle result in the accumulation of mutations as well as severe mtDNA depletion in double knockout mice [87]. This seems counterintuitive considering that a more fragmented mitochondrial network might stimulate selective mitophagy and thus would help in selecting against mutant mtDNA molecules.…”

Section: (E) Putting the Theories To The Testmentioning

confidence: 99%

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

Busch

Kowald

Spelbrink

2014

Phil. Trans. R. Soc. B

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Mammalian mtDNA encodes for 13 core proteins of oxidative phosphorylation. Mitochondrial DNA mutations and deletions cause severe myopathies and neuromuscular diseases. Thus, the integrity of mtDNA is pivotal for cell survival and health of the organism. We here discuss the possible impact of mitochondrial fusion and fission on mtDNA maintenance as well as positive and negative selection processes. Our focus is centred on the important question of how the quality of mtDNA nucleoids can be assured when selection and mitochondrial quality control works on functional and physiological phenotypes constituted by oxidative phosphorylation proteins. The organelle control theory suggests a link between phenotype and nucleoid genotype. This is discussed in the light of new results presented here showing that mitochondrial transcription factor A/nucleoids are restricted in their intramitochondrial mobility and probably have a limited sphere of influence. Together with recent published work on mitochondrial and mtDNA heteroplasmy dynamics, these data suggest first, that single mitochondria might well be internally heterogeneous and second, that nucleoid genotypes might be linked to local phenotypes (although the link might often be leaky). We discuss how random or site-specific mitochondrial fission can isolate dysfunctional parts and enable their elimination by mitophagy, stressing the importance of fission in the process of mtDNA quality control. The role of fusion is more multifaceted and less understood in this context, but the mixing and equilibration of matrix content might be one of its important functions.

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Dynamics of nucleoid structure regulated by mitochondrial fission contributes to cristae reformation and release of cytochrome c

Cited by 198 publications

References 35 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

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

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