Proteostasis perturbation destabilizes respiratory complex assembly-intermediates via aggregation of subunits

Abstract

Proteostasis is maintained by optimum expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers widespread protein aggregation and loss of function. Here, we perturbed proteostasis by blocking proteasome-mediated protein degradation and investigated proteome partitioning from soluble to insoluble fraction. Aggregation of Respiratory Chain Complex (RCC) subunits highlights the early destabilization event as revealed by proteome redistribution. Sequence analyses followed by microscopy suggest that low complexity regions at the N-terminus are capable to facilitate aggregation of RCC subunits. As a result, respiratory complex assembly process is impaired due to destabilization of sub-complexes marking the onset of mitochondrial dysfunction and ROS accumulation. Redistribution of Histone proteins and their modifications indicated reprogramming of transcription as adaptive response. Together, we demonstrate susceptibility of RCC subunits to aggregation under multiple proteotoxic stresses providing an explanation for the simultaneous deregulation of proteostasis and bioenergetics in age-related degenerative conditions.