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Ischemia‐reperfusion (I‐R) injury is the most common cause of acute kidney injury. In experiments involving primary human renal proximal tubular epithelial cells (RPTECs) exposed to anoxia‐reoxygenation, we explored the hypothesis that mitochondrial malate dehydrogenase‐2 (MDH‐2) inhibition redirects malate metabolism from the mitochondria to the cytoplasm, towards the malate‐pyruvate cycle and reversed malate‐aspartate shuttle. Colorimetry, fluorometry, and western blotting showed that MDH2 inhibition accelerates the malate‐pyruvate cycle enhancing cytoplasmic NADPH, thereby regenerating the potent antioxidant reduced glutathione. It also reversed the malate‐aspartate shuttle and potentially diminished mitochondrial reactive oxygen species (ROS) production by transferring electrons, in the form of NADH, from the mitochondria to the cytoplasm. The excessive ROS production induced by anoxia‐reoxygenation led to DNA damage and protein modification, triggering DNA damage and unfolded protein response, ultimately resulting in apoptosis and senescence. Additionally, ROS induced lipid peroxidation, which may contribute to the process of ferroptosis. Inhibiting MDH‐2 proved effective in mitigating ROS overproduction during anoxia‐reoxygenation, thereby rescuing RPTECs from death or senescence. Thus, targeting MDH‐2 holds promise as a pharmaceutical strategy against I‐R injury. [ABSTRACT FROM AUTHOR]

COVID‐19 and ME/CFS present with some similar symptoms, especially physical and mental fatigue. In order to understand the basis of these similarities and the possibility of underlying common genetic components, we performed a systematic review of all published genetic association and cohort studies regarding COVID‐19 and ME/CFS and extracted the genes along with the genetic variants investigated. We then performed gene ontology and pathway analysis of those genes that gave significant results in the individual studies to yield functional annotations of the studied genes using protein analysis through evolutionary relationships (PANTHER) VERSION 17.0 software. Finally, we identified the common genetic components of these two conditions. Seventy‐one studies for COVID‐19 and 26 studies for ME/CFS were included in the systematic review in which the expression of 97 genes for COVID‐19 and 429 genes for ME/CFS were significantly affected. We found that ACE, HLA‐A, HLA‐C, HLA‐DQA1, HLA‐DRB1, and TYK2 are the common genes that gave significant results. The findings of the pathway analysis highlight the contribution of inflammation mediated by chemokine and cytokine signaling pathways, and the T cell activation and Toll receptor signaling pathways. Protein class analysis revealed the contribution of defense/immunity proteins, as well as protein‐modifying enzymes. Our results suggest that the pathogenesis of both syndromes could involve some immune dysfunction. [ABSTRACT FROM AUTHOR]