Mitochondria are the central power stations of the cell involved with a myriad of cell signalling pathways
that contribute for whole health status of the cell. It is a well known fact that not only mitochondrial genome
encodes for mitochondrial proteins but there are several other mitochondrial specific proteins encoded by nuclear
genome which regulate plethora of cell catabolic and anabolic process. Anterograde pathways include nuclear
gene encoded proteins and their specific transport into the mitochondria and regulation of mitochondrial homeostasis.
The retrograde pathways include crosstalk between the mitochondria and cytoplasmic proteins. Indeed,
ATP dependent and independent proteases are identified to be very critical in balancing anterograde to retrograde
signalling and vice versa to maintain the cell viability or cell death. Different experimental studies conducted on
silencing the genes of these proteases have shown embryonic lethality, cancer cells death, increased hepatic glucose
output, insulin tolerance, increased protein exclusion bodies, mitochondrial dysfunction, and defect in mitochondrial
biogenesis, increased inflammation, Apoptosis etc. These experimental studies included from eubacteria
to eukaryotes. Hence, many lines of theories proposed these proteases are conservative from eubacteria to
eukaryotes. However, the regulation of these proteases at gene level is not clearly understood and still research is
warranted. In this review, we articulated the origin and regulation of these proteases and the cross talk between
the nucleus and mitochondria vice versa, and highlighted the role of these proteases in diabetes and diabetic complications
in human diseases.