The Mystery of Extramitochondrial Proteins Lysine Succinylation.

Christos Chinopoulos

doi:10.3390/ijms22116085

Abstract

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.

Highlights

Succinylation of lysine residues is a post-translational modification occurring in hundreds of proteins which can happen enzymatically or non-enzymatically [1,2,3,4,5,6,7]
All of the aforementioned reactions are connected under the following scheme: cells perform glycolysis during which NADH is formed by glyceraldehyde-3-phosphate dehydrogenase (GAPDH), eventually yielding pyruvate; pyruvate may enter mitochondria under conditions supporting oxidative phosphorylation, otherwise becoming lactate and NAD+, the latter supporting GAPDH reaction; MDH1 may support GAPDH by means of providing NAD+, especially in cells with mitochondrial dysfunction [96]; the malate/aspartate shuttle would be the means of transferring the reducing equivalent of NADH made by GAPDH to mitochondria, for the purpose of its oxidation in the electron transport chain
The lack of succinate-CoA ligase and ketoglutarate dehydrogenase complex (KGDHC) subunits precluding the possibility of enzymatic activity, and formation of succinyl-CoA to an appreciable extent (GABA shunt, along with ketone body metabolism, does not encompass succinyl-CoA while it is on low-flux pathways), raises the question as to how there can be protein lysine succinylation in adult human glia

Summary

Background

Succinylation of lysine residues is a post-translational modification occurring in hundreds of proteins which can happen enzymatically or non-enzymatically [1,2,3,4,5,6,7]. It is a common misconception that succinyl-CoA is exclusively produced inside the mitochondrial matrix by either (i) α-ketoglutarate dehydrogenase complex (KGDHC) (ii) the reversal of succinate-CoA ligase (SUCL); (iii) the catabolism of valine, isoleucine, methionine, thymine, and oddnumber chain fatty acids (and perhaps propionate); or iv) through the reaction catalyzed by 3-oxoacid CoA-transferase 1 (OXCT1), see Figure 1. The notion that glial cells in the adult human brain are known to lack KGDHC and succinate-CoA ligase subunits in their mitochondria, yet exhibit robust pancellular protein lysine succinylation, is emphasized.

Lysine Succinylation Inside and Outside Mitochondria

Extramitochondrial Sites of Succinyl-CoA Production

Intraperoxisomal Routes of Succinyl-CoA Production

Glia in the Adult Human Brain Lack Succinyl-CoA and KGDHC Subunits

Glia in the Adult Human Brain Express Enzymes Supporting Peroxisomal

Conclusions