Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1

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• 作者：Ivana Matic^c ; ¹ ; Stefania Cocco^e ; ¹ ; ² ; Caterina Ferraina^c ; ^d ; Rebeca Martin-Jimenez^a ; Fulvio Florenzano^e ; James Crosby^a ; ² ; Ramona Lupi^e ; ² ; Giusy Amadoro^e ; Claire Russell^a ; Giuseppe Pignataro^f ; ^g ; Lucio Annunziato^f ; ^g ; Andrey Y. Abramov^g ; Michelangelo Campanella^a ; ^b ; ^c ; ^d ; ^{mcampanella@rvc.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ferrutinin (PubChem ; CID 354654) ; Cyclosporine A (PubChem CID ; 5284373) ; FCCP (PubChem ; CID 3330) ; Methylthiazoletetrazolium (PubChem CID ; 64965) ; Tetramethylrhodamine methyl ester perchlorate (PubChem CID ; 11755725) ; Magnesim green (PubChem CID ; 197702)
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：103
• 期：Complete
• 页码：56-68
• 全文大小：3664 K

文摘

The mitochondrial ATPase Inhibitory Factor 1 (hereafter referred to as IF₁) blocks the reversal of the F₁F_o-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:F₁F_o-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 hypoxia/ischemia and the mitochondrial membrane potential (ΔY_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.