Succinate at the Crossroad of Metabolism and Angiogenesis: Roles of SDH, HIF1α and SUCNR1

Abstract

Angiogenesis is an essential process by which new blood vessels develop from existing ones. While adequate angiogenesis is a physiological process during, for example, tissue repair, insufficient and excessive angiogenesis stands on the pathological side. Fine balance between pro- and anti-angiogenic factors in the tissue environment regulates angiogenesis. Identification of these factors and how they function is a pressing topic to develop angiogenesis-targeted therapeutics. During the last decade, exciting data highlighted non-metabolic functions of intermediates of the mitochondrial Krebs cycle including succinate. Among these functions is the contribution of succinate to angiogenesis in various contexts and through different mechanisms. As the concept of targeting metabolism to treat a wide range of diseases is rising, in this review we summarize the mechanisms by which succinate regulates angiogenesis in normal and pathological settings. Gaining a comprehensive insight into how this metabolite functions as an angiogenic signal will provide a useful approach to understand diseases with aberrant or excessive angiogenic background, and may provide strategies to tackle them.

Complex II ambiguities—FADH2 in the electron transfer system

“…In CII, it is even covalently and thus permanently bound to the enzyme during the catalytic cycle when the redox state is regenerated in each enzymatic turnover, as documented in early reports ( 35 ) and summarized in classical textbooks ( 36 , 37 ). Structural studies of CII have expanded our knowledge of the mechanism of enzyme assembly ( 13 ), enzyme structure ( 38 , 39 , 40 ), kinetic regulation of CII activity ( 41 , 42 ), and associated pathologies ( 3 , 26 , 27 , 28 , 29 ).…”

“…In cancer tissues, CII plays a key role in metabolic remodeling ( 23 , 24 ). Beyond its role in electron transfer in the TCA cycle and the membrane-ETS, CII and succinate serve multiple functions in metabolic signaling ( 25 , 26 , 27 ). CII is thus a target of current pharmacological developments ( 28 , 29 ).…”

Cellular succinate metabolism and signaling in inflammation: implications for therapeutic intervention

“…It is located within the inner mitochondrial membrane ( 23 ) and facilitates the conversion of succinate to fumarate while simultaneously reducing ubiquinone (UQ) to ubiquinol (UQH2) and flavin adenine dinucleotide (FAD) to FADH2—critical steps in ATP production ( 3 , 24 ). Under hypoxic conditions, SDH activity diminishes, leading to the reversal of electron flow and enabling fumarate to serve as the terminal electron acceptor in the ETC, resulting in succinate accumulation ( 2 , 25 ). Chouchani et al.…”

“…However, when unresolved, this process can transition into chronic inflammation ( 1 ). A burgeoning area of research focuses on the intersection of metabolic changes and inflammation ( 2 ). Central to this discussion is succinate, a tricarboxylic acid (TCA) cycle intermediate primarily found in the mitochondrial matrix.…”

An evolving view of complex II—noncanonical complexes, megacomplexes, respiration, signaling, and beyond

“…Potentially due to the activation of these pathways, SUCNR1 stimulation by succinate has been linked to several types of cancers. SUCNR1 may be involved in a number of succinate-associated health effects including ischemia-reperfusion injury, hypertension, inflammation, rheumatoid arthritis, nonalcoholic fatty liver disease, angiogenesis, and exercise-induced muscle remodeling ( 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 ). These SUCNR1-dependent processes could explain how complex II, which controls cellular levels of the agonist, succinate, is the only respiratory enzyme that regulates metabolism or acts as a tumor suppressor ( 170 , 171 ).…”