The Mystery of Extramitochondrial Proteins Lysine Succinylation

Lysine succinylation is a post-translational modification which alters protein function in both physiological and pathological processes. Mindful that it requires succinyl-CoA, a metabolite formed within the mitochondrial matrix that cannot permeate the inner mitochondrial membrane, the question arises as to how there can be succinylation of proteins outside mitochondria. The present mini-review examines pathways participating in peroxisomal fatty acid oxidation that lead to succinyl-CoA production, potentially supporting succinylation of extramitochondrial proteins. Furthermore, the influence of the mitochondrial status on cytosolic NAD⁺ availability affecting the activity of cytosolic SIRT5 iso1 and iso4—in turn regulating cytosolic protein lysine succinylations—is presented. Finally, the discovery that glia in the adult human brain lack subunits of both alpha-ketoglutarate dehydrogenase complex and succinate-CoA ligase—thus being unable to produce succinyl-CoA in the matrix—and yet exhibit robust pancellular lysine succinylation, is highlighted.