Dietary CoQ10 Ameliorates Age‐Related Megakaryocyte Dysfunction via COPS3 ‐Mediated Activation of Autophagy

ABSTRACT Age‐related megakaryocyte (MK) dysfunction disrupts platelet production and may increase thrombotic risk, but whether coenzyme Q10 (CoQ10) restores MK homeostasis through autophagy remains unclear. Male C57BL/6J mice aged 1, 9, 15, 19, 21, or 23 months received CoQ10 for 12 weeks. Bone marrow MK proliferation, CD41/CD61 expression, DNA polyploidy, autophagy‐associated proteins, and platelet phenotypes were evaluated. H 2 O 2 ‐induced senescent MEG‐01 cells were used for pharmacological modulation with rapamycin and LY294002, bafilomycin A1‐based autophagic flux assays, and COPS3 knockdown. CoQ10 enhanced MK proliferation, maturation, and polyploidization in aged mice. Changes in the LC3‐II/LC3‐I ratio and p62 in bone marrow MKs were consistent with enhanced autophagy. Proteomic analysis identified increased COPS3 abundance in MKs from CoQ10‐treated 24‐month‐old mice. In senescent MEG‐01 cells, responses to rapamycin and LY294002 supported the involvement of autophagy‐related signaling in the effects of CoQ10. CoQ10 increased COPS3 expression even under autophagy‐inhibitory conditions and produced greater bafilomycin A1‐sensitive LC3‐II accumulation, supporting increased autophagic flux. COPS3 knockdown attenuated CoQ10‐induced changes in autophagy‐associated markers and partially diminished its effects on MK maturation and polyploidization, indicating that COPS3 contributes to, but may not solely mediate, these responses. CoQ10 did not alter platelet counts in naturally aged mice but was associated with reduced platelet aggregation and activation. Together, these findings suggest that CoQ10 ameliorates age‐related MK dysfunction and platelet hyperreactivity, in part through COPS3‐associated autophagy regulation. These findings provide a mechanistic basis for further investigation of CoQ10 as a nutritional strategy for age‐related platelet dysfunction.