Role of AMBRA1 in mitophagy regulation: emerging evidence in aging-related diseases.

ABSTRACT

Aging is a gradual and irreversible physiological process that significantly increases the risks of developing a variety of pathologies, including neurodegenerative, cardiovascular, metabolic, musculoskeletal, and immune system diseases. Mitochondria are the energy-producing organelles, and their proper functioning is crucial for overall cellular health. Over time, mitochondrial function declines causing an increased release of harmful reactive oxygen species (ROS) and DNA, which leads to oxidative stress, inflammation and cellular damage, common features associated with various age-related pathologies. The impairment of mitophagy, the selective removal of damaged or dysfunctional mitochondria by autophagy, is relevant to the development and progression of age-related diseases. The molecular mechanisms that regulates mitophagy levels in aging remain largely uncharacterized. AMBRA1 is an intrinsically disordered scaffold protein with a unique property of regulating the activity of both proliferation and autophagy core machineries. While the role of AMBRA1 during embryonic development and neoplastic transformation has been extensively investigated, its functions in post-mitotic cells of adult tissues have been limited due to the embryonic lethality caused by AMBRA1 deficiency. Recently, a key role of AMBRA1 in selectively regulating mitophagy in post-mitotic cells has emerged. Here we summarize and discuss these results with the aim of providing a comprehensive view of the mitochondrial roles of AMBRA1, and how defective activity of AMBRA1 has been functionally linked to mitophagy alterations observed in age-related degenerative disorders, including muscular dystrophy/sarcopenia, Parkinson diseases, Alzheimer diseases and age-related macular degeneration.

KEYWORDS:

• Aging
• aging-related diseases
• AMBRA1
• autophagy
• mitochondria
• mitophagy

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Additional information

Funding

This study was supported by grants from Ministry of Health: Ricerca Corrente 2024 LINEA 3 – PROGETTO 2 and Ricerca Finalizzata PNRR-MAD-2022-12375755 to GMF. We acknowledge co-funding from Next Generation EU through the Italian Ministry of University and Research, in the context of the National Recovery and Resilience Plan, Investment PE8 – Project Age-It: “Ageing Well in an Ageing Society” to Gian Maria Fimia, co-financed by the Next Generation EU (DM 1557 11.10.2022) CUP B53C22004090006, and PE6 “Heal Italia” to Mauro Piacentini CUP E83C22004670001. We also acknowledge AIRC (IG26394 to GMF). We also acknowledge funds from 5x1000 tax donation to MDR.