CHCM1/CHCHD6, Novel Mitochondrial Protein Linked to Regulation of Mitofilin and Mitochondrial Cristae Morphology

An, Jing; Shi, Jingxue; He, Qiaojun; Lui, King-Shan; Liu, Yuxin; Huang, Ying; Sheikh, M. Saeed

doi:10.1074/jbc.m111.277103

Cited by 114 publications

(144 citation statements)

References 40 publications

(56 reference statements)

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…In mammals, Mic60 (Mitofilin/IMMT), Mic10 (MINOS1), Mic19 (CHCHD3/MINOS3) and Mic25 (CHCHD6) have been identified to be main subunits of MICOS complex. [15][16][17] We then study the effect of the knockdown of Mic60/Mitofilin, Mic19/CHCHD3, Mic10/MINOS1, Mic25/CHCHD6 or Mic25/CHCHD6 plus Mic19/CHCHD3, respectively, on mitochondrial cristae architecture in mouse embryonic fibroblasts (MEFs) by transmission electron microscope. In shMic60 (short hairpin-mediated RNA interference to Mic60), shMic19 or shMic10 MEFs, most of mitochondrial cristae junctions were lost, but little onion-like cristae structure was found ( Figure 1A and Supplementary Figure 1A); in addition, mitochondrial cristae junctions were moderately reduced in shMic25 MEFs ( Figure 1A and Supplementary Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Mic25/CHCHD6 is highly homologous with Mic19/CHCHD3 in mammalian, 17 we then examined the effect of Mic25 and Mic19 double knockdown on mitochondrial cristae structure. As shown in Figure 1A, Supplementary Figures 1A and B, shMic25 slightly reduced mitochondrial cristae junctions, and Mic25 and Mic19 double knockdown have the similar effect on the loss of mitochondrial cristae or cristae junctions with shMic19, suggesting that Mic19/CHCHD3 is more critical than Mic25/CHCHD6 in organizing mitochondrial cristae structure.…”

Section: Resultsmentioning

confidence: 99%

“…In mammals, five subunits of MICOS have already been identified, including Mic60 (Mitofilin/IMMT), Mic10 (MINOS1), Mic19 (CHCHD3/MINOS3), Mic25 (CHCHD6/CHCM1) and Mic27 (APOOL). [15][16][17][18] However, the physiological functions of MICOS and how MICOS is assembled in mammals are largely unknown.The maintenance of mitochondrial protein homeostasis is critical for mitochondrial functions. Mitochondrial inner membrane i-AAA protease Yme1L is a key regulator in the quality control of mitochondrial proteins.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Twin CX 9 C proteins are characterized by a cysteine-rich motif that forms two disulfide bonds required for stabilization of their eponymous coiled coil-helix-coiled coil-helix (CHCH) domain (Cavallaro , 2010 ). CHCHD6 and CHCHD3 have similar sizes (235 and 227 amino acids, respectively), corresponding domain organizations with the CHCH fold near the C-terminus and an overall sequence identity of 36 % (Cavallaro , 2010 ; An et al , 2012 ). Knockdown of either protein in cultured cells results in similar phenotypes, including reduced growth rates, impaired mitochondrial function and loss of mitofilin.…”

Section: Aim13/chch-3/chchd3 and Chchd6mentioning

confidence: 91%

“…Instead, it has a predicted N-myristoylation site and is peripherally associated to the intermembrane space side of the inner membrane (Harner et al , 2011 ;Hoppins et al , 2011 ;von der Malsburg et al , 2011 ). Human mitofilin was shown to interact with two different putatively myristoylated peripheral inner membrane proteins located in the intermembrane space, the twin CX 9 C proteins CHCHD3 (MINOS3) and CHCHD6 (CHCM1) ( Figure 2B) (Xie et al , 2007 ;Darshi et al , 2011 ;Alkhaja et al , 2012 ;An et al , 2012 ;Ott et al , 2012 ). Twin CX 9 C proteins are characterized by a cysteine-rich motif that forms two disulfide bonds required for stabilization of their eponymous coiled coil-helix-coiled coil-helix (CHCH) domain (Cavallaro , 2010 ).…”

Section: Aim13/chch-3/chchd3 and Chchd6mentioning

confidence: 99%

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

Zerbes¹,

Klei

Veenhuis

et al. 2012

Biological Chemistry

118

View full text Add to dashboard Cite

: Mitofilin proteins are crucial organizers of mitochondrial architecture. They are located in the inner mitochondrial membrane and interact with several protein complexes of the outer membrane, thereby generating contact sites between the two membrane systems of mitochondria. Within the inner membrane, mitofilins are part of hetero-oligomeric protein complexes that have been termed the mitochondrial inner membrane organizing system (MINOS). MINOS integrity is required for the maintenance of the characteristic morphology of the inner mitochondrial membrane, with an inner boundary region closely apposed to the outer membrane and cristae membranes, which form large tubular invaginations that protrude into the mitochondrial matrix and harbor the enzyme complexes of the oxidative phosphorylation machinery. MINOS deficiency comes along with a loss of crista junction structures and the detachment of cristae from the inner boundary membrane. MINOS has been conserved in evolution from unicellular eukaryotes to humans, where alterations of MINOS subunits are associated with multiple pathological conditions.

show abstract

OPA1 functionally interacts with MIC60 but is dispensable for crista junction formation

et al. 2016

View full text Add to dashboard Cite

Edited by Miguel De la RosaRemodeling of crista junctions (CJs) is observed in numerous human disorders and during apoptosis. The functional interplay of OPA1 and MIC60, two key players in this context, is unclear. We show that OPA1 modulates cristae morphology but is dispensable for CJ formation. MIC60 is strongly enriched at CJs, whereas OPA1 is distributed evenly across the inner membrane. MIC60 levels are increased in OPA1À/À cells which show increased cellular resistance to apoptosis induction. Endogenous OPA1 and MIC60 show a physical interaction. Overall, we suggest that the regulation of CJ remodeling during apoptosis is mediated via an interplay between OPA1 and MIC60.

show abstract

CHCM1/CHCHD6, Novel Mitochondrial Protein Linked to Regulation of Mitofilin and Mitochondrial Cristae Morphology

Cited by 114 publications

References 40 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

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

OPA1 functionally interacts with MIC60 but is dispensable for crista junction formation

Contact Info

Product

Resources

About