Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca²⁺ Transfer to...

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Metabolic Stress

Background:

• Mitochondria are dynamic organelles regulating cellular physiology.
• Calcium ions (Ca2+) are key regulators of mitochondrial function.
• Disruptions in Ca2+ transfer to mitochondria induce metabolic stress and cell death.

Purpose of the Study:

• To investigate the mechanisms underlying mitochondrial fragmentation caused by impaired Ca2+ transfer.
• To identify key molecular players involved in metabolic stress-induced mitochondrial fragmentation.

Main Methods:

• Investigated mitochondrial fragmentation in cells with inhibited IP3R-mediated Ca2+ transfer.
• Analyzed changes in NAD+/NADH ratio, SIRT1, AMPK, and cortactin.
• Utilized cortactin knockdown and actin polymerization inhibitors.

Main Results:

• Impaired Ca2+ transfer induced DRP-1 independent mitochondrial fragmentation.
• Early fragmentation involved increased NAD+/NADH ratio and SIRT1 activation.
• SIRT1 deacetylated cortactin, promoting actin polymerization and fragmentation.
• AMPK activation followed and drove fragmentation.
• Cortactin manipulation or actin inhibition prevented fragmentation.

Conclusions:

• SIRT1 is a novel regulator of mitochondrial fragmentation during metabolic stress.
• The study reveals a pathway involving SIRT1, cortactin, and the actin cytoskeleton in mitochondrial fragmentation.
• This pathway is independent of DRP-1 and linked to bioenergetic status.