Targeting mitophagy in combined therapies of haematological malignancies

Abstract

Mitophagy is a selective form of autophagy that eliminates mitochondria, and ispart of a larger network of mitochondrial quality control processes that respond tomitochondrial damage. Treatment of haematological malignancies often involves drugs thatultimately cause cell death by mitochondrial injury and initiation of apoptosis. Thus,mitophagy is a potential cause of resistance to anticancer drugs that target the mitochondria(mitocans). Since mitophagy is integrated to mitochondrial biogenesis, mitochondrial fissionand fusion, the bioenergetics profile and metabolic reprogramming of tumour cells, theblockage of mitophagy may not be sufficient to overcome resistance. In addition, themitochondrial unfolded protein response and the outer mitochondrial membrane associateddegradation have extensive crosstalk with mitophagy, and advanced forms of neoplasmswill require targeting both systems. Proteasome inhibitors and vinca alkaloids target manyof the critical steps involved in resistance to mitocans, while inducers of mitochondrialturnover (biogenesis and mitophagy) like valproic acid have a variable effect depending onmetabolic reprograming and the activity of oxidative phosphorylation of tumour cells. Herewe discuss the mechanisms of mitophagy and its associated mechanisms, and discuss itsapplication to the rationale of targeted combined therapies of low and high-grade B-cellneoplasms.