Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor

Abstract

SUMMARY The removal of unwanted or damaged mitochondria by autophagy, a process called mitophagy, is essential for key events in development, cellular homeostasis, tumor suppression, and prevention of neurodegeneration and aging. However, the precise mechanisms of mitophagy remain uncertain. Here, we identify the inner mitochondrial membrane protein, prohibitin 2 (PHB2), as a crucial mitophagy receptor involved in targeting mitochondria for autophagic degradation. PHB2 binds the autophagosomal membrane-associated protein LC3 through an LC3-interaction region (LIR) domain upon mitochondrial depolarization and proteasome-dependent outer membrane rupture. PHB2 is required for Parkin-induced mitophagy in mammalian cells and for the clearance of paternal mitochondria after embryonic fertilization in C. elegans. Our findings pinpoint a conserved mechanism of eukaryotic mitophagy and demonstrate a function of prohibitin 2 that may underlie its roles in physiology, aging, and disease.

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

“…The authors conclude that Prohibitin 2 acts as a MIM mitophagy receptor which becomes accessible to LC3 after MOM rupture during Pink1/Parkin mitophagy. The binding to LC3 then promotes the efficient removal of dysfunctional mitochondria (Wei et al, 2017). It is remarkable to note that in this way Prohibitin 2 acts as a true mitophagy receptor located in the MIM, but at the same time Prohibitin 2-mediated mitophagy remains fully dependent on the Pink1/Parkin pathway, suggesting an interplay of these two pathways.…”

“…One of the youngest members of the family of putative mitophagy receptors, Prohibitin 2/PHB2, was found in a screening for LC3-interacting proteins under mitophagy inducing conditions (Wei et al, 2017). At first sight this appears unexpected as Prohibitin 2 is located in the MIM as a part of the ring-shaped, heterodimeric Prohibitin 1/2 mega-complex which has important roles in mitochondrial biogenesis including degradation of mitochondrial membrane proteins, controlling mitochondrial protein folding, and cristae morphogenesis (reviewed in ArtalSanz and Tavernarakis, 2009;Bavelloni et al, 2015).…”

“…At first sight this appears unexpected as Prohibitin 2 is located in the MIM as a part of the ring-shaped, heterodimeric Prohibitin 1/2 mega-complex which has important roles in mitochondrial biogenesis including degradation of mitochondrial membrane proteins, controlling mitochondrial protein folding, and cristae morphogenesis (reviewed in ArtalSanz and Tavernarakis, 2009;Bavelloni et al, 2015). Prohibitin 2 was shown to bind LC3-II, but not GABARAP with its LIR motif in a Pink1/Parkin-dependent manner and knockdown of the protein inhibited mitochondrial degradation (Wei et al, 2017). The Prohibitin 2-mediated mitophagy is dependent on proteasomal degradation and rupture of the MOM.…”

From fever to immunity: A new role for IGFBP‐6?

“…If and how such direct effects of IGFBPs impact on cell metabolism remains to be established. Intriguingly, one of the recognized IGFBP‐6 receptor is prohibitin‐2 (PBH2) 57, 58. Although PBH2 is located as a single transmembrane helix spanning protein in the cell membrane, the majority of PBH2 is located in a ring‐shaped oligomer in the inner mitochondrial membrane where it functions as a crucial mitophagy receptor 57.…”

Modificações em proteínas induzidas por compostos eletrofílicos. possível papel em esclerose lateral amiotrófica

“…Ainda nesse mesmo conjunto de proteínas, a presença da aldeído desidrogenase mitocondrial nos animais ELA pré-sintomáticos pode sugerir indícios de uma atuação deletéria dos aldeídos provenientes de um desequilíbrio no balanço redox mitocondrial, é interessante destacar que essas evidencias de ruptura no equilíbrio redox ocorrem antes dos sintomas. Outra proteína relevante, ainda neste grupo de indivíduos, é a proibitina 2, que atua na marcação mitocondrial para autofagia, é importante frisar nesse contexto de compartimentalização celular, que processos biológicos diferentes parecem ocorrer na mesma organela (mitocôndria), sugerindo talvez uma relação entre a doença e os processos redox mitocondriais, já que a aldeído desidrogenase e esta última proteína são mitocondriais (Wei, et al, 2017).…”