Evolving paradigms on the interplay of mitochondrial Hsp70 chaperone system in cell survival and senescence

The role of mitochondria within a cell has grown beyond being the prime source of cellular energy to one of the major signaling platforms. Recent evidence provides several insights into the crucial roles of mitochondrial chaperones in regulating the organellar response to external triggers. The mitochondrial Hsp70 (mtHsp70/Mortalin/Grp75) chaperone system plays a critical role in the maintenance of proteostasis balance in the organelle. Defects in mtHsp70 network result in attenuated protein transport and misfolding of polypeptides leading to mitochondrial dysfunction. The functions of Hsp70 are primarily governed by J-protein cochaperones. Although human mitochondria possess a single Hsp70, its multifunctionality is characterized by the presence of multiple specific J-proteins. Several studies have shown a potential association of Hsp70 and J-proteins with diverse pathological states that are not limited to their canonical role as chaperones. The role of mitochondrial Hsp70 and its co-chaperones in disease pathogenesis has not been critically reviewed in recent years. We evaluated some of the cellular interfaces where Hsp70 machinery associated with pathophysiological conditions, particularly in context of tumorigenesis and neurodegeneration. The mitochondrial Hsp70 machinery shows a variable localization and integrates multiple components of the cellular processes with varied phenotypic consequences. Although Hsp70 and J-proteins function synergistically in proteins folding, their precise involvement in pathological conditions is mainly idiosyncratic. This machinery is associated with a heterogeneous set of molecules during the progression of a disorder. However, the precise binding to the substrate for a specific physiological response under a disease subtype is still an undocumented area of analysis.