SLP2 coordinates MICOS assembly and cristae morphogenesis via MIC13 and YME1L

The MICOS complex subunit MIC13 is essential for mitochondrial cristae organization. Mutations in MIC13 cause severe mitochondrial hepato-encephalopathy displaying defective cristae morphology and loss of the MIC10-subcomplex. Here we identified SLP2 as a novel interacting partner of MIC13 and decipher a critical role of SLP2 for MICOS assembly at distinct steps. SLP2 provides a large interaction hub for MICOS subunits and loss of SLP2 imparted YME1L-mediated proteolysis of MIC26 and drastic alterations in cristae morphology. We further identified a MIC13-specific role in stabilizing the MIC10-subcomplex via a MIC13-YME1L axis. SLP2 together with the stabilized MIC10-subcomplex promotes efficient assembly of the MIC60-subcomplex forming the MICOS-MIB complex. Consistently, super-resolution nanoscopy showed a dispersed distribution of the MIC60 in cells lacking SLP2 and MIC13. Our study reveals converging and interdependent assembly pathways for the MIC10- and MIC60-subcomplexes which are controlled in two ways, the MIC13-YME1L and the SLP2-YME1L axes, revealing mechanistic insights of these factors in cristae morphogenesis. These results will be helpful in understanding the human pathophysiology linked to mutations in MIC13 or its interaction partners

Comorbidities and inflammation associated with ovarian cancer and its influence on SARS-CoV-2 infection

Abstract Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide is a major public health concern. Cancer patients are considered a vulnerable population to SARS-CoV-2 infection and may develop several COVID-19 symptoms. The heightened immunocompromised state, prolonged chronic pro-inflammatory milieu coupled with comorbid conditions are shared in both disease conditions and may influence patient outcome. Although ovarian cancer (OC) and COVID-19 are diseases of entirely different primary organs, both diseases share similar molecular and cellular characteristics in their microenvironment suggesting a potential cooperativity leading to poor outcome. In COVID-19 related cases, hospitalizations and deaths worldwide are lower in women than in males; however, comorbidities associated with OC may increase the COVID-19 risk in women. The women at the age of 50-60 years are at greater risk of developing OC as well as SARS-CoV-2 infection. Increased levels of gonadotropin and androgen, dysregulated renin-angiotensin-aldosterone system (RAAS), hyper-coagulation and chronic inflammation are common conditions observed among OC and severe cases of COVID-19. The upregulation of common inflammatory cytokines and chemokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-2, IL-6, IL-10, interferon-γ-inducible protein 10 (IP-10), granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), macrophage colony-stimulating factor (M-CSF), among others in the sera of COVID-19 and OC subjects suggests potentially similar mechanism(s) involved in the hyper-inflammatory condition observed in both disease states. Thus, it is conceivable that the pathogenesis of OC may significantly contribute to the potential infection by SARS-CoV-2. Our understanding of the influence and mechanisms of SARS-CoV-2 infection on OC is at an early stage and in this article, we review the underlying pathogenesis presented by various comorbidities of OC and correlate their influence on SARS-CoV-2 infection

MIC26 and MIC27 are bona fide subunits of the MICOS complex in mitochondria and do not exist as glycosylated apolipoproteins

Impairments of mitochondrial functions are linked to human ageing and pathologies such as cancer, cardiomyopathy, neurodegeneration and diabetes. Specifically, aberrations in ultrastructure of mitochondrial inner membrane (IM) and factors regulating them are linked to diabetes. The development of diabetes is connected to the ‘Mitochondrial Contact Site and Cristae Organising System’ (MICOS) complex which is a large membrane protein complex defining the IM architecture. MIC26 and MIC27 are homologous apolipoproteins of the MICOS complex. MIC26 has been reported as a 22 kDa mitochondrial and a 55 kDa glycosylated and secreted protein. The molecular and functional relationship between these MIC26 isoforms has not been investigated. In order to understand their molecular roles, we depleted MIC26 using siRNA and further generated MIC26 and MIC27 knockouts (KOs) in four different human cell lines. In these KOs, we used four anti-MIC26 antibodies and consistently detected the loss of mitochondrial MIC26 (22 kDa) and MIC27 (30 kDa) but not the loss of intracellular or secreted 55 kDa protein. Thus, the protein assigned earlier as 55 kDa MIC26 is nonspecific. We further excluded the presence of a glycosylated, high-molecular weight MIC27 protein. Next, we probed GFP- and myc-tagged variants of MIC26 with antibodies against GFP and myc respectively. Again, only the mitochondrial versions of these tagged proteins were detected but not the corresponding high-molecular weight MIC26, suggesting that MIC26 is indeed not post-translationally modified. Mutagenesis of predicted glycosylation sites in MIC26 also did not affect the detection of the 55 kDa protein band. Mass spectrometry of a band excised from an SDS gel around 55 kDa could not confirm the presence of any peptides derived from MIC26. Taken together, we conclude that both MIC26 and MIC27 are exclusively localized in mitochondria and that the observed phenotypes reported previously are exclusively due to their mitochondrial function