Mitochondrial inner membrane fusion depends on the dynaminrelated GTPase OPA1 and the function of OPA1 is regulated by proteolytic cleavage. The mitochondrial proteases Yme1L and OMA1 cleave OPA1 at S2 and S1 sites, respectively. Here, we show that OMA1 is cleaved to a short form (S-OMA1) by itself upon mitochondrial membrane depolarization; S-OMA1 is degraded quickly but could be stabilized by CCCP treatment or Prohibitin knockdown in cells. In addition, OMA1 processing is positively correlated with OPA1 cleavage at the S1 site and the regulation of mitochondrial morphology. Thus, our results reveal the molecular mechanism for OMA1 activation toward OPA1 processing.

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...

Branching morphogenesis is a fundamental program for tissue patterning. We show that active YAP, a key mediator of Hippo signaling, is distributed throughout the murine lung epithelium and loss of epithelial YAP severely disrupts branching. Failure to branch is restricted to regions where YAP activity is removed. This suggests that YAP controls local epithelial cell properties. In support of this model, mechanical force production is compromised and cell proliferation is reduced in Yap mutant lungs. We propose that defective force generation and insufficient epithelial cell number underlie the branching defects. Through genomic analysis, we also uncovered a feedback control of pMLC levels, which is critical for mechanical force production, likely through the direct induction of multiple regulators by YAP. Our work provides a molecular pathway that could control epithelial cell properties required for proper morphogenetic movement and pattern formation.DOI: http://dx.doi.org/10.7554/eLife.21130.001

Mitochondrial cristae are critical for efficient oxidative phosphorylation, however, how cristae architecture is precisely organized remains largely unknown. Here, we discovered that Mic19, a core component of MICOS (mitochondrial contact site and cristae organizing system) complex, can be cleaved at N-terminal by mitochondrial protease OMA1 under certain physiological stresses. Mic19 directly interacts with mitochondrial outer-membrane protein Sam50 (the key subunit of SAM complex) and inner-membrane protein Mic60 (the key component of MICOS complex) to form Sam50-Mic19-Mic60 axis, which dominantly connects SAM and MICOS complexes to assemble MIB (mitochondrial intermembrane space bridging) supercomplex for mediating mitochondrial outer-and inner-membrane contact. OMA1-mediated Mic19 cleavage causes Sam50-Mic19-Mic60 axis disruption, which separates SAM and MICOS and leads to MIB disassembly. Disrupted Sam50-Mic19-Mic60 axis, even in the presence of SAM and MICOS complexes, causes the abnormal mitochondrial morphology, loss of mitochondrial cristae junctions, abnormal cristae distribution and reduced ATP production. Importantly, Sam50 displays punctate distribution at mitochondrial outer membrane, and acts as an anchoring point to guide the formation of mitochondrial cristae junctions. Therefore, we propose that Sam50-Mic19-Mic60 axis-mediated SAM-MICOS complexes integration determines mitochondrial cristae architecture.