Improved Supra-Organization Is A Conformational And Functional Adaptation Of Respiratory Complexes

Abstract

Multiple surveillance mechanisms accelerate proteasome mediated degradation of misfolded proteins to prevent protein aggregation inside and outside mitochondria. But how cells safeguard mitochondrial function despite increased protein aggregation during proteasome inactivation? Here, using two-dimensional complexome profiling, we extensively characterize the dynamic states of respiratory complexes (RCs) in proteasome-inhibited cells.We report that RC-subunits are increasingly integrated into supra-organizations to optimize catalytic activity simultaneous to their aggregation inside mitochondria. Complex-II (CII) and CV are incorporated into oligomers. CI, CIII, and CIV subcomplexes are associated into holocomplexes followed by integration into supercomplexes. Time-course experiments reveal that the core (CI+CIII 2 ) stoichiometry of supercomplex (I+III 2 +IV) is preserved during earlystress while CIV composition varies. Simultaneously, increased CI-activity suggests conformational optimization of supercomplexes for better function. Re-establishment of steady-state stoichiometry and relative increase in supercomplex-quantity consolidates functional adaptation during prolonged proteasome-inhibition. Together, we name this preemptive adaptive mechanism as 'improved Supra-organization of Respiratory Complexes' (iSRC). We find that iSRC is active in multiple protein-unfolding stresses, in multiple celltypes that differ in proteostatic and metabolic demands, and reversible upon stresswithdrawal.

Kingdom-specific lipid unsaturation shapes up sequence evolution in membrane arm subunits of eukaryotic respiratory complexes

“…Respiratory complex I (CI) is the first and largest complex in the respiratory chain 34,35 . Human CI is composed of 44 subunits with 17 subunits in the matrix arm, 23 subunits embedded into inner mitochondrial membrane (IMM), and 4 subunits exposed to the inter- membrane space (IMS) ( Fig.…”