The spatio-temporal organization of mitochondrial F1FO ATP synthase in cristae depends on its activity mode

Salewskij, Kirill; Rieger, Bettina; Hager, Frances; Arroum, Tasnim; Duwe, Patrick; Villalta, Jimmy; Colgiati, Sara; Richter, Christian; Psathaki, Olympia E.; Enrı́quez, José Antonio; Dellmann, Timo; Busch, Karin B.

doi:10.1016/j.bbabio.2019.148091

Cited by 37 publications

(39 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cristae are not static structures [ 30 ]; they are dynamically formed in a manner dependent on a variety of known and unknown factors which control ATP synthesis rates [ 31 ]. That said, the main proteins that exert some control over the cristae’s shape are the mitochondrial contact site and cristae organizing system (MICOS) [ 32 - 34 ], optic atrophy factor 1 (OPA1) [ 33 , 35 , 36 ], and ATP synthase [ 32 , 37 - 39 ]. The MICOS proteins are necessary to form proper cristae junctions, a region in mitochondria that connects the inner boundary membrane to the cristae lumen.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Effects of Calcium Overload on Mitochondrial Ultrastructural Remodeling

et al. 2021

View full text Add to dashboard Cite

Mitochondrial cristae are dynamic invaginations of the inner membrane and play a key role in its metabolic capacity to produce ATP. Structural alterations caused by either genetic abnormalities or detrimental environmental factors impede mitochondrial metabolic fluxes and lead to a decrease in their ability to meet metabolic energy requirements. While some of the key proteins associated with mitochondrial cristae are known, very little is known about how the inner membrane dynamics are involved in energy metabolism. In this study, we present a computational strategy to understand how cristae are formed using a phase-based separation approach of both the inner membrane space and matrix space, which are explicitly modeled using the Cahn–Hilliard equation. We show that cristae are formed as a consequence of minimizing an energy function associated with phase interactions which are subject to geometric boundary constraints. We then extended the model to explore how the presence of calcium phosphate granules, entities that form in calcium overload conditions, exert a devastating inner membrane remodeling response that reduces the capacity for mitochondria to produce ATP. This modeling approach can be extended to include arbitrary geometrical constraints, the spatial heterogeneity of enzymes, and electrostatic effects to mechanize the impact of ultrastructural changes on energy metabolism.

show abstract

Section: Introductionmentioning

confidence: 99%

Modeling the Effects of Calcium Overload on Mitochondrial Ultrastructural Remodeling

et al. 2021

View full text Add to dashboard Cite

show abstract

“…We stained cells with antibodies directed against either of two IM proteins, ATPase B (ATPB) or Prohibitin 2 (PHB2). Complex V, ATP synthase (stained by ATPB), is thought to be under-represented along the IBM and to be enriched in cristae under normal growth conditions, where it contributes to membrane curvature [30]. PHB2, in complex with Prohibitin 1, is an abundant scaffold component of the IM [31].…”

Section: Mitochondria In A549 Cells Frequently Exhibit Bloated Morphomentioning

confidence: 99%

A549 cells contain enlarged mitochondria with independently functional clustered mtDNA nucleoids

2021

View full text Add to dashboard Cite

Mitochondria are commonly viewed as highly elongated organelles with regularly spaced mtDNA genomes organized as compact nucleoids that generate the local transcripts essential for production of mitochondrial ribosomes and key components of the respiratory chain. In contrast, A549 human lung carcinoma cells frequently contain apparently swollen mitochondria harboring multiple discrete mtDNA nucleoids and RNA processing granules in a contiguous matrix compartment. While this seemingly aberrant mitochondrial morphology is akin to “mito-bulbs” previously described in cells exposed to a variety of genomic stressors, it occurs in A549 cells under typical culture conditions. We provide a detailed confocal and super-resolution microscopic investigation of the incidence of such mito-bulbs in A549 cells. Most mito-bulbs appear stable, engage in active replication and transcription, and maintain respiration but feature an elevated oxidative environment. High concentrations of glucose and/or L-glutamine in growth media promote a greater incidence of mito-bulbs. Furthermore, we demonstrate that treatment of A549 cells with TGFβ suppresses the formation of mito-bulbs while treatment with a specific TGFβ pathway inhibitor substantially increases incidence. This striking heterogeneity of mitochondrial form and function may play an important role in a variety of diseases involving mitochondrial dysfunction.

show abstract

“…Thus, these data suggest that in WT HeLa cells a subpopulation of ATP synthase is in the reverse mode. Under OXPHOS conditions (Salewskij et al, 2019;Weissert et al, 2020), IF1 is required to block this. Unexpectedly, also IF1-H49K expressing cells had lower mitochondrial ATP levels than WT cells (but higher levels than IF1-KO cells).…”

Section: If1 Is Required To Optimize Mitochondrial Atp Production Ratmentioning

confidence: 99%

“…For studying the effect of ATP synthase on local pH, an IF1-KO cell line (Salewskij et al, 2019) and a cell line expressing the constitutively active variant IF1-H49K were generated (Garcia-Aguilar and Cuezva, 2018; Schnizer et al, 1996). Levels of IF1 were determined by immuno-detection of the IF1 peptide levels from the different cell lines confirmed successful knockout and expression IF1-H49K, respectively (Supplementary Figure S3A,B).…”

Section: Inhibition Of Atp Synthase With Oligomycin and If1 Disclosesmentioning

confidence: 99%

Mitochondrial F₁F_OATP synthase determines the local proton motive force in cristae tips

Rieger

Arroum

Villalta

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

The classical view of oxidative phosphorylation is that a proton motive force PMF generated by the respiratory chain complexes fuels ATP synthesis. Under glycolytic conditions, ATP synthase in its reverse mode also can contribute to the PMF. Here, we dissected the two functions of ATP synthase and the role of the inhibitory factor 1 (IF1) under different metabolic conditions in detail. pH profiles of mitochondrial sub-compartments were recorded with high spatial resolution in live mammalian cells by positioning a pH-sensor directly at F1 and FO of ATP synthase, complex IV and in the matrix. Our results clearly show that ATP synthase activity is substantially controlling the PMF and that IF1 is essential under OXPHOS conditions to prevent reverse ATP synthase activity due to an almost negligible delta pH.

show abstract

The spatio-temporal organization of mitochondrial F1FO ATP synthase in cristae depends on its activity mode

Cited by 37 publications

References 69 publications

Modeling the Effects of Calcium Overload on Mitochondrial Ultrastructural Remodeling

Modeling the Effects of Calcium Overload on Mitochondrial Ultrastructural Remodeling

A549 cells contain enlarged mitochondria with independently functional clustered mtDNA nucleoids

Mitochondrial F₁F_OATP synthase determines the local proton motive force in cristae tips

Contact Info

Product

Resources

About

The spatio-temporal organization of mitochondrial F1FO ATP synthase in cristae depends on its activity mode

Cited by 37 publications

References 69 publications

Modeling the Effects of Calcium Overload on Mitochondrial Ultrastructural Remodeling

Modeling the Effects of Calcium Overload on Mitochondrial Ultrastructural Remodeling

A549 cells contain enlarged mitochondria with independently functional clustered mtDNA nucleoids

Mitochondrial F1FOATP synthase determines the local proton motive force in cristae tips

Contact Info

Product

Resources

About

Mitochondrial F₁F_OATP synthase determines the local proton motive force in cristae tips