Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells

Otera, Hidenori; Wang, Chunxin; Cleland, Megan M.; Setoguchi, Kiyoko; Yokota, Sadaki; Youle, Richard J.; Mihara, Katsuyoshi

doi:10.1083/jcb.201007152

Cited by 936 publications

(1,069 citation statements)

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“…Disruption of the CLS1 locus in HCT116 cells was based on previously published procedures 47,48 with some modifications. Vectors were a gift of R. Youle.…”

Section: Methodsmentioning

confidence: 99%

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

et al. 2016

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During apoptosis, proapoptotic BAX and BAK trigger mitochondrial outer membrane (MOM) permeabilization by a mechanism that is not yet fully understood. BH3-only proteins such as tBID, together with lipids of the MOM, are thought to play a key role in BAX and BAK activation. In particular, cardiolipin (CL) has been shown to stimulate tBID-induced BAX activation in vitro. However, it is still unclear whether this process also relies on CL in the cell, or whether it is more dependent on MTCH2, a proposed receptor for tBID present in the MOM. To address this issue, we deleted both alleles of cardiolipin synthase in human HCT116 cells by homologous recombination, which resulted in a complete absence of CL. The CL-deficient cells were fully viable in glucose but displayed impaired oxidative phosphorylation and an inability to grow in galactose. Using these cells, we found that CL was not required for either tBID-induced BAX activation, or for apoptosis in response to treatment with TRAIL. Downregulation of MTCH2 in HCT116 cells also failed to prevent recruitment of tBID to mitochondria in apoptotic conditions. However, when both CL and MTCH2 were depleted, a significant reduction in tBID recruitment was observed, suggesting that in HCT116 cells, CL and MTCH2 can have redundant functions in this process.

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“…Disruption of the CLS1 locus in HCT116 cells was based on previously published procedures 47,48 with some modifications. Vectors were a gift of R. Youle.…”

Section: Methodsmentioning

confidence: 99%

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

et al. 2016

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“…Next, the membrane of the elongated peroxisome forms constrictions by a not yet clearly defined mechanism [6]. Final fragmentation requires several fission proteins, including the tail-anchored (TA) proteins hFis1 (fission 1), Mff (mitochondrial fission factor) and the cytosolic Drp1/DLP1 (dynamin-related protein 1) [7][8][9][10][11][12]. These proteins are also essential fission factors at the mitochondrial outer membrane (MOM).…”

Section: Introductionmentioning

confidence: 99%

Charcot‐Marie‐Tooth disease‐associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission

et al. 2013

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Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail-anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re-expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1-induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission.

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“…Mitochondrial division is mediated by Drp1, which is mainly located in the cytosol. Drp1 is recruited to the mitochondrial surface by other outer membrane proteins (James et al, 2003;Yoon et al, 2003;Gandre-Babbe and van der Bliek, 2008;Otera et al, 2010;Palmer et al, 2011), where it assembles into spiral structures around mitochondria to induce fission of the mitochondrial membrane (Yoon et al, 2001;Lackner et al, 2009). The importance of mitochondrial dynamics to human health is highlighted by studies showing that mutations in Mfn2 and Opa1 underlie neurological disorders, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, whereas a mutation in Drp1 causes neurodevelopmental abnormalities (Alexander et al, 2000;Delettre et al, 2000;Züchner et al, 2004;Waterham et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage

Kageyama¹,

Zhang²,

Roda³

et al. 2012

J Exp Med

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Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells

Abstract: Localization of the dynamin-related GTPase Drp1 to mitochondria relies on the mitochondrial fission factor Mff.

Cited by 936 publications

References 64 publications

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

Charcot‐Marie‐Tooth disease‐associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission

Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage

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