{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPeroxisome proliferator‐activated receptor gamma coactivator‑1α (PGC‑1α) is emerging as a master regulator of cellular energy metabolism, driving mitochondrial biogenesis and orchestrating oxidative metabolism across a variety of tissues. It is induced by environmental cues such as exercise, cold exposure, and nutrient stress, thereby enhancing fatty acid oxidation, oxidative phosphorylation, and antioxidant defence. In skeletal muscle, decreased expression of PGC‑1α associates with insulin resistance and type 2 diabetes, and epigenetic modifications of its promoter further limit mitochondrial gene expression, contributing to metabolic disturbances."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, PGC‑1α confers a bioenergetic advantage to tumor cells by reprogramming metabolism toward enhanced mitochondrial respiration. In invasive and metastatic cancers such as melanoma and breast cancer, upregulation of PGC‑1α promotes oxidative phosphorylation, mitochondrial biogenesis, and reactive oxygen species detoxification, thereby enabling tumor cells to cope with energetic stress and facilitating metastasis while influencing therapeutic responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPGC‑1α also plays critical roles in the nervous system. In Huntington’s disease, mutant huntingtin protein represses PGC‑1α transcription, leading to mitochondrial dysfunction and increased neuronal vulnerability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Conversely, in depression, exercise‐induced upregulation of skeletal muscle PGC‑1α stimulates a peripheral metabolic pathway that converts kynurenine into kynurenic acid—a metabolite that cannot enter the brain—thereby conferring neuroprotection against stress‐induced depressive phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, alternative promoter usage and splicing of the PGC‑1α transcript in skeletal muscle yield isoforms with distinct functional properties. One such isoform specifically induces insulin‑like growth factor 1 (IGF‑1) expression while repressing myostatin, thus driving muscle hypertrophy and enhancing strength, which underscores the versatile role of PGC‑1α in adaptive muscle remodelling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPost‐translational regulation further fine‑tunes PGC‑1α activity. Deacetylases such as SIRT3 and SIRT1, together with upstream kinases like AMPK, modulate its transcriptional coactivator function to ensure balanced mitochondrial biogenesis and efficient reactive oxygen species clearance. These layers of regulation are essential for maintaining mitochondrial quality and cellular redox homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn renal tissues, PGC‑1α is pivotal for recovery from ischemic injury by upregulating enzymes involved in de novo NAD biosynthesis. This adaptive response improves mitochondrial function and energy balance, thereby protecting the kidney against ischemia‑induced failure."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, PGC‑1α regulates the expression of the myokine irisin via its downstream target FNDC5, linking exercise to systemic metabolic benefits. This axis further exemplifies the broad impact of PGC‑1α in translating environmental and physiological stimuli into coordinated transcriptional programmes that optimize organismal energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mary Elizabeth Patti, Atul J Butte, Sarah Crunkhorn, et al. 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