Suppressing the dark side of autophagy

Area of Science:

• Cellular Biology
• Aging Research
• Mitochondrial Biology

Background:

• Lifespan extension in model organisms often relies on increased autophagy.
• However, the role of autophagy becomes complex when mitochondrial function is impaired.

Purpose of the Study:

• To investigate the detrimental effects of autophagy when mitochondrial membrane integrity is compromised.
• To explore the conserved mechanisms linking autophagy, mitochondrial permeability, and lifespan.

Main Methods:

• Utilized genetic manipulation in *C. elegans* to study mutants lacking mTORC2 and SGK-1.
• Assessed lifespan, autophagy levels, and mitochondrial permeability (VDAC-1 levels) in wild-type and mutant organisms.
• Examined the impact of mitochondrial permeability on established autophagy-dependent lifespan extension paradigms and ischemia-reperfusion injury.

Main Results:

• Mutants lacking mTORC2 or SGK-1 exhibited shortened lifespan despite increased autophagy, which was restored by reducing autophagy.
• These mutants showed impaired mitochondrial permeability linked to elevated VDAC-1 protein.
• Induction of mitochondrial permeability reversed all tested autophagy-dependent lifespan extensions and worsened injury outcomes.

Conclusions:

• Autophagy, when combined with compromised mitochondrial permeability, is detrimental to lifespan.
• This detrimental interplay is conserved across species, from nematodes to mammals.
• Targeting mitochondrial integrity is crucial for understanding and potentially modulating autophagy's role in aging and injury.