The Soluble Form of Bax Regulates Mitochondrial Fusion via MFN2 Homotypic Complexes

Abstract

Summary In mammals, fusion of the mitochondrial outer membrane is controlled by two DRPs, MFN1 and MFN2, that function in place of a single outer membrane DRP, Fzo1 in yeast. We addressed the significance of two mammalian outer membrane fusion DRPs using an in vitro mammalian mitochondrial fusion assay. We demonstrate that heterotypic MFN1/MFN2 trans complexes possess greater efficacy in fusion as compared to homotypic MFN1 or MFN2 complexes. In addition, we show that the soluble form of the pro-apoptotic Bcl2 protein, Bax, positively regulates mitochondrial fusion exclusively through homotypic MFN2 trans complexes. Together, these data demonstrate functional and regulatory distinctions between MFN1 and MFN2 and provide insight into their unique physiological roles.

NP1 Regulates Neuronal Activity-Dependent Accumulation of BAX in Mitochondria and Mitochondrial Dynamics

“…In addition, knockdown of NP1 did not prevent the mitochondrial fragmentation observed in Bax knock-out mice. These results indicate that NP1 contributes to mitochondrial fragmentation during apoptosis by facilitating the activation of BAX and neutralizing in turn the positive effect that soluble BAX has on mitochondrial fusion in healthy cells (Hoppins et al, 2011). This interpretation is consistent with the mechanistic model that proposes a mutually exclusive relationship between the role of BAX in the positive regulation of mitochondrial fusion and its role in apoptosis (Sheridan et al, 2008;Cleland et al, 2011;Hoppins et al, 2011).…”

“…These results indicate that NP1 contributes to mitochondrial fragmentation during apoptosis by facilitating the activation of BAX and neutralizing in turn the positive effect that soluble BAX has on mitochondrial fusion in healthy cells (Hoppins et al, 2011). This interpretation is consistent with the mechanistic model that proposes a mutually exclusive relationship between the role of BAX in the positive regulation of mitochondrial fusion and its role in apoptosis (Sheridan et al, 2008;Cleland et al, 2011;Hoppins et al, 2011). Overall, the present results indicate that NP1 is required for mitochondrial fragmentation during apoptosis and suggest that activity-dependent regulation of NP1 expression is part of a mechanism that transforms the physiological action of proteins that regulate mitochondrial dynamics in healthy cells such as BAX into a pathological pro-apoptotic function.…”

“…In addition to its role in apoptosis, BAX regulates mitochondrial fusion-fission dynamics through a direct interaction with proteins involved in mitochondrial morphogenesis (Sheridan et al, 2008;Cleland et al, 2011;Hoppins et al, 2011). Based on our finding that NP1 interacts with BAX, we investigated the influence of NP1 on mitochondrial length and we found that NP1 also regulates activity-dependent mitochondrial dynamics.…”

“…Other pro-apoptotic proteins associated with neurodegenerative diseases, such as mutant forms of Huntingtin and superoxide dismutase as well as A␤, have been reported to induce mitochondrial fragmentation and impair mitochondrial trafficking (for review, see Rintoul and Reynolds, 2010). Although the relationship between mitochondrial dynamics and transport is still not well understood, the observation that NP1 interacts with BAX, which interacts in turn with Mitofusin 2 (Hoppins et al, 2011), a protein that is necessary for mitochondrial transport through Miro 1, a GTPase localized in mitochondria (Misko et al, 2010), suggests that NP1 may interfere with anterograde transport by preventing the association of BAX with the Miro/Milton protein complex. This hypothesis is currently under investigation.…”

Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

“…In the latter study a mouse model expressing photo-activatable mito-Dendra-2 was generated that could help quantify mitochondrial dynamics in a gene-, tissue-, and age-dependent manner in vivo. Also, in vitro mammalian cell fusion assays have become available, which could be used to detect redox-, cell-type-, and tissue-specific differences regulating mitochondrial fusion [56][57][58].…”