Inner mitochondrial membrane compartmentalization: Dynamics across scales

Busch, Karin B.

doi:10.1016/j.biocel.2020.105694

Cited by 25 publications

(15 citation statements)

References 55 publications

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“…The ATP synthase was shown, notably in mammals, to accumulate at the inner cristae membrane (ICM) where its oligomers are involved in the shaping of the membrane (Strauss et al , 2008; Davies et al , 2011; Jiko et al , 2015; Wilkens et al , 2013; Busch, 2020). An as-yet unresolved question is whether the biogenesis of the enzyme takes place at the inner boundary membrane (IBM) that faces the outer membrane, and then moves into the ICM, or whether assembly occurs within the ICM.…”

Section: Resultsmentioning

confidence: 99%

TMEM70 forms oligomeric scaffolds within mitochondrial cristae promotingin situassembly of mammalian ATP synthase proton channel

Bahri

Buratto

Rojo

et al. 2020

Preprint

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Mitochondrial ATP-synthesis is catalyzed by a F1Fo-ATP synthase, an enzyme of dual genetic origin enriched at the edge of cristae where it plays a key role in their structure/stability. The enzyme’s biogenesis remains poorly understood, both from a mechanistic and a compartmentalization point of view. The present study provides novel molecular insights into this process through investigations on a human protein called TMEM70 with an unclear role in the assembly of ATP synthase. A recent study has revealed the existence of physical interactions between TMEM70 and the subunit c (Su.c), a protein present in 8 identical copies forming a transmembrane oligomeric ring (c-ring) within the ATP synthase proton translocating domain (FO). Herein we analyzed the ATP-synthase assembly in cells lacking TMEM70, mitochondrial DNA or F1 subunits and observe a reciprocal dependence of TMEM70 and Su.c levels, regardless of the status of other ATP synthase subunits or of mitochondrial bioenergetics. Immunoprecipitation and two-dimensional blue-native/SDS-PAGE reveal that TMEM70 forms large oligomers composed of 8 TMEM70 dimers and that TMEM70 oligomers interact with Su.c not yet incorporated into ATP synthase complexes. Moreover, discrete TMEM70-Su.c complexes with increasing Su.c contents can be detected, suggesting a role for TMEM70 oligomers in the gradual assembly of the c-ring. Furthermore, we demonstrate using expansion super-resolution microscopy the specific localization of TMEM70 at the inner cristae membrane, distinct from the MICOS component MIC60. Taken together, our results show that TMEM70 oligomers provide a scaffold for c-ring assembly and that mammalian ATP synthase is assembled within inner cristae membranes.

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Section: Resultsmentioning

confidence: 99%

TMEM70 forms oligomeric scaffolds within mitochondrial cristae promotingin situassembly of mammalian ATP synthase proton channel

Bahri

Buratto

Rojo

et al. 2020

Preprint

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“…The OXPHOS complexes were shown, notably in mammals, to accumulate in cristae with a differential enrichment of respiratory chain complexes within the laminar part of cristae and of ATP synthase at the edge of cristae (6,7,9,42,43). What are the mechanisms and operating forces underlying such a compartmentalization is a challenging question.…”

Section: Discussionmentioning

confidence: 99%

“…The ATP synthase was shown, notably in mammals, to accumulate at the inner cristae membrane (ICM) where its oligomers are involved in the shaping of this membrane (6,7,9,42,43). An as-yet unresolved question is whether the biogenesis of the ATP synthase takes place at the inner boundary membrane (IBM) that faces the outer membrane, and then moves into the ICM, or whether assembly occurs directly within the ICM.…”

Section: Tmem70 Is An Inner Membrane Protein Specifically Localized Imentioning

confidence: 99%

TMEM70 forms oligomeric scaffolds within mitochondrial cristae promoting in situ assembly of mammalian ATP synthase proton channel

Bahri

Buratto

Rojo

et al. 2021

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Mitochondrial ATP-synthesis is catalyzed by a F1Fo-ATP synthase, an enzyme of dual genetic origin enriched at the edge of cristae where it plays a key role in their structure/stability. The enzyme's biogenesis remains poorly understood, both from a mechanistic and a compartmentalization point of view. The present study provides novel molecular insights into this process through investigations on a human protein called TMEM70 with an unclear role in the assembly of ATP synthase. A recent study has revealed the existence of physical interactions between TMEM70 and the subunit c (Su.c), a protein present in 8 identical copies forming a transmembrane oligomeric ring (c-ring) within the ATP synthase proton translocating domain (FO). Herein we analyzed the ATP-synthase assembly in cells lacking TMEM70, mitochondrial DNA or F1 subunits and observe a reciprocal dependence of TMEM70 and Su.c levels, regardless of the status of other ATP synthase subunits or of mitochondrial bioenergetics. Immunoprecipitation and two-dimensional blue-native/SDS-PAGE reveal that TMEM70 forms large oligomers composed of 8 TMEM70 dimers and that TMEM70 oligomers interact with Su.c not yet incorporated into ATP synthase complexes. Moreover, discrete TMEM70-Su.c complexes with increasing Su.c contents can be detected, suggesting a role for TMEM70 oligomers in the gradual assembly of the cring. Furthermore, we demonstrate using expansion super-resolution microscopy the specific localization of TMEM70 at the inner cristae membrane, distinct from the MICOS component MIC60. Taken together, our results show that TMEM70 oligomers provide a scaffold for c-ring assembly and that mammalian ATP synthase is assembled within inner cristae membranes.

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“…The respiratory complexes are mainly found in the cristae membrane [56]. Further, sophisticated analysis of diffusion and directionality of movement of single complexes by super resolution microscopy revealed that all the complexes are trapped in the laminar part of cristae, except CII which is also found in the inner boundary membrane [59] (Figure 1). It has to be noticed that CII is a rather small complex and does not associate in supramolecular assemblies with other complexes.…”

Section: Oxphos Optimization By the Inner Membrane Architecturementioning

confidence: 98%

Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

Rugolo

Zanna

Ghelli

2021

Life

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The mitochondrial respiratory chain encompasses four oligomeric enzymatic complexes (complex I, II, III and IV) which, together with the redox carrier ubiquinone and cytochrome c, catalyze electron transport coupled to proton extrusion from the inner membrane. The protonmotive force is utilized by complex V for ATP synthesis in the process of oxidative phosphorylation. Respiratory complexes are known to coexist in the membrane as single functional entities and as supramolecular aggregates or supercomplexes (SCs). Understanding the assembly features of SCs has relevant biomedical implications because defects in a single protein can derange the overall SC organization and compromise the energetic function, causing severe mitochondrial disorders. Here we describe in detail the main types of SCs, all characterized by the presence of complex III. We show that the genetic alterations that hinder the assembly of Complex III, not just the activity, cause a rearrangement of the architecture of the SC that can help to preserve a minimal energetic function. Finally, the major metabolic disturbances associated with severe SCs perturbation due to defective complex III are discussed along with interventions that may circumvent these deficiencies.

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Inner mitochondrial membrane compartmentalization: Dynamics across scales

Cited by 25 publications

References 55 publications

TMEM70 forms oligomeric scaffolds within mitochondrial cristae promotingin situassembly of mammalian ATP synthase proton channel

TMEM70 forms oligomeric scaffolds within mitochondrial cristae promotingin situassembly of mammalian ATP synthase proton channel

TMEM70 forms oligomeric scaffolds within mitochondrial cristae promoting in situ assembly of mammalian ATP synthase proton channel

Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

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