{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nIn skeletal muscle, COX6A2—a tissue‐specific subunit of mitochondrial complex IV—plays a pivotal role in modulating energy metabolism. Studies have shown that loss of COX6A2 leads to increased energy expenditure, a shift toward more oxidative muscle fiber types, elevated reactive oxygen species, and constitutive AMPK activation. These adaptations collectively protect against high‐fat diet–induced obesity, insulin resistance, and glucose intolerance by promoting respiratory uncoupling in muscle fibers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the brain, COX6A2 is critical for the high-energy demands of fast-spiking parvalbumin-positive interneurons. Its restricted expression in these cells is essential for maintaining cellular ATP levels, perineuronal net integrity, and proper neuronal circuit integration. Redox dysregulation leads to upregulation of miR-137—which in turn downregulates COX6A2—and is associated with impaired mitophagy and accumulation of damaged mitochondria. These molecular alterations correspond to disrupted gamma oscillations in cortical networks, findings that are reflected in both experimental models and early psychosis patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in muscle and neural tissues, COX6A2 contributes to pancreatic β‐cell function. Under glucotoxic conditions, diminished Cox6a2 expression leads to increased oxidative stress in β‐cells, which is linked to impaired insulin secretion and glucose intolerance. Importantly, transcriptional regulation by MafA has been demonstrated to directly control COX6A2 expression, thereby connecting metabolic stress with mitochondrial dysfunction in diabetes mellitus."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Roel Quintens, Sarvjeet Singh, Katleen Lemaire, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0056719"}], "href": "https://doi.org/10.1371/journal.pone.0056719"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23460811"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23460811"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ines Khadimallah, Raoul Jenni, Jan-Harry Cabungcal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41380-021-01313-9"}], "href": "https://doi.org/10.1038/s41380-021-01313-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34686767"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34686767"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Berta Sanz-Morello, Ulrich Pfisterer, Nikolaj Winther Hansen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.2020105759"}], "href": "https://doi.org/10.15252/embj.2020105759"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32744742"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32744742"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yasuki Nagai, Taka-Aki Matsuoka, Naoki Shimo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glucotoxicity-induced suppression of Cox6a2 expression provokes β-cell dysfunction via augmented ROS production."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2021.03.148"}], "href": "https://doi.org/10.1016/j.bbrc.2021.03.148"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33839409"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33839409"}]}]}]}