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

Area of Science:

• Hepatology and cellular biology
• Molecular mechanisms of liver disease
• Mitochondrial dynamics and quality control

Background:

• Mitophagy dysfunction in hepatocytes impairs liver energy homeostasis and worsens metabolic dysfunction-associated steatotic liver disease (MASLD).
• Heat shock protein 72 (HSP72), a known chaperone, is investigated for its role in regulating mitophagy within the context of MASLD.

Purpose of the Study:

• To elucidate the role of HSP72 in controlling hepatocyte mitophagy in MASLD.
• To identify key interacting proteins and molecular mechanisms through which HSP72 influences mitophagy and MASLD progression.

Main Methods:

• Assessed mitophagy and HSP72 levels in MASLD mouse models and human liver samples.
• Utilized global and liver-specific Hsp72 knockout mice and primary hepatocytes for functional studies.
• Employed co-immunoprecipitation and LC-MS to identify HSP72 interacting proteins and analyzed PINK1 ubiquitination at specific sites.

Main Results:

• Decreased HSP72 levels correlated with suppressed mitophagy and exacerbated MASLD in mice and humans.
• HSP72 deficiency worsened MASLD and mitophagy; restoring HSP72 ameliorated these conditions.
• Peroxiredoxin 6 (PRDX6) was identified as an HSP72 interactor crucial for mitophagy; its absence led to PINK1 ubiquitination and MASLD exacerbation, while its restoration reversed these effects, highlighting PINK1 residue Lys318 (K318).

Conclusions:

• The HSP72/PRDX6 axis is essential for PINK1/Parkin-dependent mitophagy.
• This pathway plays a critical role in counteracting the progression of MASLD.