HSP72 interacts with PRDX6 to deubiquitinate mitochondrial PINK1, activating mitophagy to treat MASLD: [RETRACTED]

Plain Language Summary Background and Aims: Mitophagy dysfunction in hepatocytes impedes energy homeostasis in the liver and exacerbates metabolic dysfunction–associated steatotic liver disease (MASLD). This study investigated the novel role of heat shock protein 72 (HSP72), a classic chaperone protein, in controlling mitophagy in the livers of MASLD mice and isolated primary mouse hepatocytes. Approach and Results: Mitophagy and HSP72 expression levels in the livers of MASLD mice and humans were determined. Global or liver-specific Hsp72−/− and HSP72+/+ mice, or primary mouse hepatocytes, were used to unravel the role of HSP72 in regulating mitophagy and MASLD. Coimmunoprecipitation and LC-MS joint analysis was performed to identify HSP72-interacting protein involving mitophagy; its effect on the ubiquitination level of PTEN-induced kinase 1 (PINK1) and the crucial ubiquitinated site within PINK1 were explored and confirmed. Liver mitophagy was suppressed in MASLD mice and patients as the level of HSP72 decreased. Global or liver-specific deletion of HSP72 specifically exacerbated MASLD and suppressed mitophagy. Restoring HSP72 level in the liver activated mitophagy and ameliorated MASLD. The observations were further confirmed in isolated primary mouse hepatocytes with genetic manipulation of HSP72. Peroxiredoxin 6 (PRDX6) is identified as an interactive protein of HSP72 and is correlated with mitophagy. PRDX6 deletion ubiquitinated PINK1 and inhibited mitophagy, thereby exacerbating MASLD. Instead, restoring PRDX6 efficiently deubiquitinated PINK1, thus activating mitophagy. More importantly, residue Lys318 (K318) of PINK1 was revealed as a priority site for its ubiquitination in response to PRDX6 regulation. Conclusions: These data suggest that the HSP72/PRDX6 axis is indispensable for PINK1/Parkin-dependent mitophagy to counteract MASLD. Export Plain Language SummaryThis study examined how the chaperone protein heat shock protein 72 (HSP72) controls mitophagy (selective removal of damaged mitochondria) in metabolic dysfunction–associated steatotic liver disease (MASLD). In both MASLD mice and patients, liver mitophagy and HSP72 levels were reduced. Deleting Hsp72 in mice, either globally or only in the liver, suppressed mitophagy and worsened MASLD, while restoring HSP72 reactivated mitophagy and improved disease. Mechanistic studies in primary hepatocytes identified peroxiredoxin 6 (PRDX6) as an HSP72-interacting protein that regulates PINK1 ubiquitination at Lys318 (K318) and thereby controls PINK1/Parkin-dependent mitophagy. The HSP72/PRDX6 axis is therefore critical for protecting the liver against MASLD. Text is machine generated and may contain inaccuracies. FAQ