Mitochondrial Complex II: At the Crossroads

Recent research points to a major role of complex II (CII) in various aspects of cell biology, being at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. CII therefore represents a branching point of two essential mitochondrial pathways. Dysfunction of succinate dehydrogenase (SDH) leads to accumulation of succinate, which is categorized as an oncometabolite and signaling molecule. CII is a major player in mitochondrial reactive oxygen species (ROS) generation and contributes ROS either directly or indirectly via reverse electron transfer (RET). Genetic mutations as well as epigenetic regulation of the SDHx genes are associated with several pathological conditions. Similarly, both metabolic and epigenetic malfunctions have emerged as the underlying molecular mechanisms of the pathologies. Several novel accessory proteins have been identified as crucial for the biogenesis of the SDH complex. They are referred to as assembly factors and emerging data show mutations in their genes to be linked to dysfunction of CII with clinical presentation. Modulation of SDH function under various metabolic conditions could be utilized as a promising therapeutic target. Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited. Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited. assessory proteins that help insert prosthetic groups into the subunits of mitochondrial RCs, including CII, resulting in their full assembly and acquisition of function; also help stabilize subunits of CII or intermediate complexes before complete assembly of CII. altered expression of genes mediated by simple modification of bases in specific regions of genes (e.g., methylation of CpG islands). a decarboxylation product of the TCA intermediate metabolite cis-aconitate in a reaction catalyzed by immune-responsive gene 1 (IRG1); has antimicrobial activity and inhibits SDH. innate immune cells involved in the host defense system that are divided into two major subtypes: M1 and M2 cells. M1 cells are activated by classical stimuli such as lipopolysaccharide (LPS), interferon gamma (IFNγ), and bacteria. Activated M1 macrophages are marked by an increase in glycolysis, a decrease in mitochondrial respiratory activity, and a change in TCA cycle activity (mainly accumulation of succinate and citrate). M2 macrophages are activated by interleukin-4 (IL-4) and IL-13, maintaining active OXPHOS and the TCA cycle. process of generation of ATP at the expense of oxygen. a collective name for various forms of oxygen-containing small molecules (such as superoxide) that have an important function in biological systems, including regulation of various signaling pathways as well as causing damage to a variety of biologically active molecules. mitochondrial complexes located in the inner mitochondrial membrane that are involved in the movement of electrons between CI/CII and CIV via CIII and in generation of the proton motive force. from CII via UbQ to CI; a major pathway of mitochondrial ROS production.