Fig. 3.
HDAC in controlling the powerhouse through mitophagy: HDAC inhibitors (HDACis) deacetylate non-histone target p53 and subsequent downstream effector targets such as FOXO, BNIP3, HIF 1α, E2F, and Ras. The p53 deacetylation stabilizes the PINK1 in the depolarized mitochondrial membrane leading to subsequent recruitment of Parkin. Parkin-mediated ubiquitination of mitochondrial membrane proteins and subsequent interaction with autophagic adaptor molecules such as LC3 and p62 perform PINK–Parkin-mediated mitophagy. In BNIP3/NIX-mediated mitophagy, SIRT1 and HDAC regulate deacetylation of p53 and HIFs. BNIP3 dimers interact with Rheb in a Bcl-2 and Bcl-XL-dependent manner and reduce it. Reduction of free Rheb inactivates mTOR that induces autophagy. The associated downstream molecules promote mitophagosome formation. The involvement of cardiolipins as a direct mitophagic receptor promotes lipid-mediated mitophagy, whereas S1P indirectly regulates cardiolipin-mediated mitophagy. The role of C18 in ceramide-induced mitophagy is not well known; however, the intra-molecular interlink between LC3B and C18-ceramide will put forth the novel mechanism underlying the role of HDACs in ceramide-induced mitophagy