Neuroprotective coordination of cell mitophagy by the F1Fo-ATPase inhibitory factor 1 (IF1)

作者：Matic Ivana; Cocco Stefania; Ferraina Caterina; Martin Jimenez Rebeca; Florenzano Fulvio; Cro**y James; Lupi Ramona; Amadoro Giusy; Russell Claire; Pignataro Giuseppe; Annunziato Lucio; Abramov Andrey Y; Campanella Michelangelo^*

来源：Pharmacological Research, 2016, 103: 56-68.

DOI：10.1016/j.phrs.2015.10.010

• F1Fo-ATPsynthase
• IF1
• Mitophagy
• Hypoxia/ischemia
• Re-oxygenation
• Delta Psi(m)

The mitochondrial F(1)Fo-ATPase inhibitory factor 1 (IF1) blocks the reversal of the F(1)Fo-ATPsynthase to prevent detrimental consumption of cellular ATP and associated demise. Herein, we infer further its molecular physiology by assessing its protective function in neurons during conditions of challenged homeostatic respiration.
By adopting in vitro and in vivo protocols of hypoxia/ischemia and re-oxygenation, we show that a shift in the IF1:F1Fo-ATPsynthase expression ratio occurs in neurons. This increased IF1 level is essential to induce accumulation of the PTEN-induced putative kinase 1 (PINK-1) and recruitment of the mitophagic ubiquitin ligase PARK-2 to promote autophagic "control" of the mitochondrial population. In IF1 overexpressing neurons ATP depletion is reduced during hypoxiaiischemia and the mitochondrial membrane potential (Delta Y-m) resilient to re-oxygenation as well as resistant to electrogenic, Ca2+ dependent depolarization.
These data suggest that in mammalian neurons mitochondria adapt to respiratory stress by upregulating IF1, which exerts a protective role by coordinating pro-survival cell mitophagy and bioenergetics resilience.

• 出版日期2016-1