Regulated membrane remodeling by Mic60 controls formation of mitochondrial crista junctions

Hessenberger, Manuel; Zerbes, Ralf M.; Rampelt, Heike; Kunz, Séverine; Xavier, Audrey; Purfürst, Bettina; Lilie, Hauke; Pfanner, Nikolaus; Laan, Martin van der; Daumke, Oliver

doi:10.1038/ncomms15258

Cited by 87 publications

(135 citation statements)

References 68 publications

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“…Fig 5A and C)and resulted in mitochondrial fragmentation (Fig EV3A and B)(Duvezin-Caubet et al, 2006;Ishihara et al, 2006;Griparic et al, 2007). To date, the most notable of these are the family of MICOS-complex proteins(Rabl et al, 2009;Harner et al, 2011;Hoppins et al, 2011;von der Malsburg et al, 2011;Zerbes et al, 2012;Barbot et al, 2015;Friedman et al, 2015;Guarani et al, 2015;Barrera et al, 2016;Hessenberger et al, 2017;Rampelt et al, 2017;Wollweber et al, 2017) and the GTPase, Opa1(Frezza et al, 2006;Cogliati et al, 2016). To date, the most notable of these are the family of MICOS-complex proteins(Rabl et al, 2009;Harner et al, 2011;Hoppins et al, 2011;von der Malsburg et al, 2011;Zerbes et al, 2012;Barbot et al, 2015;Friedman et al, 2015;Guarani et al, 2015;Barrera et al, 2016;Hessenberger et al, 2017;Rampelt et al, 2017;Wollweber et al, 2017) and the GTPase, Opa1(Frezza et al, 2006;Cogliati et al, 2016).…”

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confidence: 99%

“…The crista-junction (CJ) modulators, MICOS complex and Opa1, regulate DΨ Cr-IBMTo determine the role of CJs and cristae architecture in the generation of DΨ Cr-IBM , we used cellular models in which proteins controlling the formation of cristae and CJs are perturbed. To date, the most notable of these are the family of MICOS-complex proteins(Rabl et al, 2009;Harner et al, 2011;Hoppins et al, 2011;von der Malsburg et al, 2011;Zerbes et al, 2012;Barbot et al, 2015;Friedman et al, 2015;Guarani et al, 2015;Barrera et al, 2016;Hessenberger et al, 2017;Rampelt et al, 2017;Wollweber et al, 2017) and…”

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confidence: 99%

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Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent

et al. 2019

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The mitochondrial membrane potential (ΔΨm) is the main driver of oxidative phosphorylation (OXPHOS). The inner mitochondrial membrane (IMM), consisting of cristae and inner boundary membranes (IBM), is considered to carry a uniform ΔΨm. However, sequestration of OXPHOS components in cristae membranes necessitates a re‐examination of the equipotential representation of the IMM. We developed an approach to monitor ΔΨm at the resolution of individual cristae. We found that the IMM was divided into segments with distinct ΔΨm, corresponding to cristae and IBM. ΔΨm was higher at cristae compared to IBM. Treatment with oligomycin increased, whereas FCCP decreased, ΔΨm heterogeneity along the IMM. Impairment of cristae structure through deletion of MICOS‐complex components or Opa1 diminished this intramitochondrial heterogeneity of ΔΨm. Lastly, we determined that different cristae within the individual mitochondrion can have disparate membrane potentials and that interventions causing acute depolarization may affect some cristae while sparing others. Altogether, our data support a new model in which cristae within the same mitochondrion behave as independent bioenergetic units, preventing the failure of specific cristae from spreading dysfunction to the rest.

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confidence: 99%

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confidence: 99%

Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent

et al. 2019

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“…The mechanisms of mitochondrial cristae biogenesis are debated and different mechanisms for this process have been suggested [21][22][23][24][25][26][27][28] . To better analyze the formation of cristae and their structure and dynamics under different cellular conditions, a new approach for high-resolution live cell imaging of mitochondrial cristae is urgently needed.…”

Section: Discussionmentioning

confidence: 99%

Live-cell STED microscopy of mitochondrial cristae

Stephan

Roesch

Riedel

et al. 2019

Preprint

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Mitochondria are highly dynamic organelles that exhibit a complex inner architecture. They exhibit a smooth outer membrane and a highly convoluted inner membrane that forms invaginations called cristae. Imaging cristae in living cells poses a formidable challenge for light microscopy. Relying on a cell line stably expressing the mitochondrial protein Cox8A fused to the SNAP-tag and using STED (stimulated emission depletion) super-resolution microscopy, we demonstrate the visualization of cristae dynamics in cultivated human cells.

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“…While several pathways can regulate the cristae in a complementary fashion, OPA1 still is the only known mitochondrial protein necessary and sufficient for inner membrane fusion. OPA1 also interacts via IMMT with a multi‐protein complex termed MICOS (mitochondrial contact site and cristae organizing system) . The MICOS complex in turn can associate with the outer membrane through binding to SAMM50, which helps coordinate the cristae junctions with the mitochondria‐ER contact sites .…”

Section: Mitochondrial Membrane Organizationmentioning

confidence: 99%

“…MICOS (mitochondrial contact site and cristae organizing system). [72][73][74] The MICOS complex in turn can associate with the outer membrane through binding to SAMM50, which helps coordinate the cristae junctions with the mitochondria-ER contact sites. [75][76][77] The F 1 F O -ATP synthase, the TOM translocase and the SAM sorting and assembly complex are also involved in this trans-organelle cristae organization.…”

Section: Opa1mentioning

confidence: 99%

Targeted OMA1 therapies for cancer

Alavi¹

2019

Intl Journal of Cancer

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The mitochondrial inner membrane proteins OMA1 and OPA1 belong to the BAX/BAK1‐dependent apoptotic signaling pathway, which can be regulated by tumor protein p53 and the prohibitins PHB and PHB2 in the context of neoplastic disease. For the most part these proteins have been studied separate from each other. Here, I argue that the OMA1 mechanism of action represents the missing link between p53 and cytochrome c release. The mitochondrial fusion protein OPA1 is cleaved by OMA1 in a stress‐dependent manner generating S‐OPA1. Excessive S‐OPA1 can facilitate outer membrane permeabilization upon BAX/BAK1 activation through its membrane shaping properties. p53 helps outer membrane permeabilization in a 2‐step process. First, cytosolic p53 activates BAX/BAK1 at the mitochondrial surface. Then, in a second step, p53 binds to prohibitin thereby releasing the restraint on OMA1. This activates OMA1, which cleaves OPA1 and promotes cytochrome c release. Clearly, OMA1 and OPA1 are not root causes for cancer. Yet many cancer cells rely on this pathway for survival, which can explain why loss of p53 function promotes tumor growth and confers resistance to chemotherapies.

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Regulated membrane remodeling by Mic60 controls formation of mitochondrial crista junctions

Cited by 87 publications

References 68 publications

Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent

Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent

Live-cell STED microscopy of mitochondrial cristae

Targeted OMA1 therapies for cancer

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