Abstract
Homologous apolipoproteins of MICOS complex, MIC26 and MIC27, show an antagonistic regulation of their protein levels, making it difficult to deduce their individual functions using a single gene deletion. We obtained single and double knockout (DKO) human cells of MIC26 and MIC27 and found that DKO show more concentric onion-like cristae with loss of CJs than any single deletion indicating overlapping roles in formation of CJs. Using a combination of complexome profiling, STED nanoscopy, and blue-native gel electrophoresis, we found that MIC26 and MIC27 are dispensable for the stability and integration of the remaining MICOS subunits into the complex suggesting that they assemble late into the MICOS complex. MIC26 and MIC27 are cooperatively required for the integrity of respiratory chain (super) complexes (RCs/SC) and the F1Fo-ATP synthase complex and integration of F1 subunits into the monomeric F1Fo-ATP synthase. While cardiolipin was reduced in DKO cells, overexpression of cardiolipin synthase in DKO restores the stability of RCs/SC. Overall, we propose that MIC26 and MIC27 are cooperatively required for global integrity and stability of multimeric OXPHOS complexes by modulating cardiolipin levels.
Highlights
Mitochondria are vital cellular organelles that perform several important functions involving energy conversion, cellular metabolism, reactive oxygen species (ROS) production, heme synthesis, calcium homeostasis, and apoptosis
We found that Single knockouts (SKOs) of MIC26 and MIC27 show moderate cristae defects when compared with double knockout (DKO) cells that show a clear increase in extent of cristae defects with accumulation of onion-like cristae
How do MIC26 and MIC27 affect MICOS complex function and thereby crista junctions (CJs) formation? Unlike the loss of MIC60, MIC10, or MIC13 that led to destabilization of either the whole or part of the MICOS subcomplex, MIC26 and MIC27 were not required for the stability of the known remaining subunits of the MICOS complex and their incorporation into higher molecular weight complexes
Summary
Mitochondria are vital cellular organelles that perform several important functions involving energy conversion, cellular metabolism, reactive oxygen species (ROS) production, heme synthesis, calcium homeostasis, and apoptosis. Cristae are compositionally and functionally distinct from the rest of the IM, called inner boundary membrane (IBM) (Vogel et al, 2006; Wurm & Jakobs, 2006), presumably due to the presence of crista junctions (CJs) which are small, pore-, or slit-like openings present at the neck of a crista (Perkins et al, 1997; Mannella et al, 2001). Cristae shape varies considerably depending on the bioenergetic demands during physiological changes and stress, including hypoxia, nutrient starvation, ROS, or induction of apoptosis (Mannella, 2006; Gomes et al, 2011; Cogliati et al, 2016; Pernas & Scorrano, 2016; Plecita-Hlavata et al, 2016; Baker et al, 2019; Dlaskova et al, 2019). Using live-cell stimulated emission depletion (STED) super-resolution nanoscopy, we recently showed that CJs and cristae undergo dynamic remodelling in a balanced and reversible manner that is MICOS complex-dependent (Kondadi et al, 2020)
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