Proteostasis is maintained by optimum expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. Here, using quantitative proteomics and microscopy we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein-destabilization event during short-term proteasome inhibition. Among these, Respiratory Chain Complex (RCC) subunits represent a group of functionally related proteins consistently forming aggregates under multiple proteostasis-stresses with varying aggregation-propensities. Sequence analysis reveals that several RCC subunits, irrespective of cleavable mitochondrial targeting sequence (MTS), contain low complexity regions (LCR) at N-terminus. Using different chimeric and mutant constructs we show that these low complexity regions partially contribute to intrinsic instability of multiple RCC subunits. Taken together, we propose that physicochemically driven aggregation of unassembled RCC subunits destabilizes their functional assembly inside mitochondria. This deregulates the biogenesis of respiratory complexes and marks the onset of mitochondrial dysfunction.