{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:38:17Z","timestamp":1786527497482,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Long COVID is frequently characterized by exertion intolerance, delayed symptom exacerbation, treatment sensitivity, and prolonged recovery. Post-exertional malaise (PEM) is often interpreted as a manifestation of low energy availability, autonomic dysfunction, immune activation, endothelial disturbance, or deconditioning. This paper proposes an additional recovery-failure mechanism for a PEM-dominant subgroup: fragile mitophagy, defined as a mismatch in which mitochondrial injury and mitophagy engagement occur but lysosomal completion of mitochondrial degradation is inadequate. Incomplete clearance could permit mitochondrial debris and danger signaling to persist and amplify oxidative, innate immune, endothelial, and neuroimmune responses after physiologic stress. The model predicts delayed crashes, progressive lowering of baseline with repeated exertion, and poor tolerance of interventions that increase mitochondrial turnover when lysosomal capacity is insufficient. Patient-derived Long COVID studies demonstrate mitochondrial, metabolic, and structural abnormalities but do not yet establish defective dynamic mitophagy flux or lysosomal completion. Hydroxychloroquine and chloroquine are used only as pharmacologic analogies showing that late autophagic flux can be impaired by disrupted lysosomal handling. Trehalose, genistein, curcumin, and the curcumin analog C1 are presented as experimental mechanistic probes because of reported effects on TFEB or autophagy-lysosome biology, not as established Long COVID treatments. The central prediction is that PEM severity will correlate more closely with impaired lysosomal completion, abnormal mitophagy flux, mitochondrial debris, and danger signaling than with baseline adenosine triphosphate (ATP) deficiency alone.<\/jats:p>","DOI":"10.3389\/fmed.2026.1905758","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:10:21Z","timestamp":1786525821000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Fragile mitophagy in long COVID: a proposed recovery-failure endotype for post-exertional malaise"],"prefix":"10.3389","volume":"13","author":[{"given":"Robert","family":"Groysman","sequence":"first","affiliation":[{"name":"Independent Researcher, Covid Institute","place":["Plano, TX, United 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