Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.
Xingjie Zhuo,Shuxian Ding,Jinhua Li,Mingcong Deng,Xinyue Zhang,Weijun Yang,Lili Gu,Qin Li
Background Ischemic stroke (IS) is a major global cause of disability and death, with its complex pathophysiology posing a significant challenge for effective therapy. Although flavonoids from Ziziphora clinopodioides Flavonoids (ZCF) have demonstrated neuroprotective potential, their comprehensive mechanisms of action remain incompletely understood. Objective The purpose of this study is to systematically elucidate the improvement effect of ZCF on ischemic stroke and its potential mechanism by integrating multi-omics analysis and in vitro and in vivo experimental verification. Methods In this study, the neuroprotective mechanism of ZCF on MCAO/R-treated SD rats and OGD/R-treated PC12 cells was studied by combining transcriptomics, non-targeted metabolomics, and molecular biology verification (Western blot, q-PCR, immunofluorescence, etc.). The key role of FUNDC1 in this pathway was verified by siRNA knockdown. Results ZCF administration significantly improved neurological function, reduced cerebral infarction volume, and reduced neuronal apoptosis. Integrated transcriptomics and metabolomics analysis found that ZCF reversed disease-related changes, and its core effects were the mitophagy and ferroptosis pathways. Mechanistically, ZCF alleviates pathological TDP-43 aggregation, activates FUNDC1-mediated mitophagy, and inhibits ferroptosis. Crucially, siRNA knockdown of FUNDC1 eliminated these protective effects. Conclusion ZCF improves ischemic stroke by enhancing FUNDC1-dependent mitophagy to remove pathological TDP-43, thereby inhibiting the mechanism of ferroptosis.
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