Why F-ATP Synthase Remains a Strong Candidate as the Mitochondrial Permeability Transition Pore

Bernardi, Paolo

doi:10.3389/fphys.2018.01543

Cited by 41 publications

(43 citation statements)

References 45 publications

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“…In HAP1-Δ(c+δ) cells, the levels of respiratory complexes I, III, and IV and oxygen consumption are reduced markedly relative to HAP1-WT cells. A similar reduction in respiratory complexes and oxygen consumption has been noted also in HAP1-Δc, -Δb, and -ΔOSCP cells (23,24), leading to the ability to generate a membrane potential to drive the uptake of Ca 2+ being questioned (34), despite clear experimental evidence that they were able to do so (23,24). Therefore, to remove any possible residual doubts about the ability of the mitochondria of HAP1-Δ(c+δ) cells to maintain a membrane potential and to accumulate pulses of exogenous Ca 2+ , it was shown here explicitly that they do, as expected, take up Ca 2+ more slowly than mitochondria in HAP1-WT cells, but the membrane potential recovers, and they accumulate Ca 2+ to the point where the PTP opens and the membrane potential collapses (SI Appendix, Figs.…”

Section: Discussionmentioning

confidence: 59%

Persistence of the permeability transition pore in human mitochondria devoid of an assembled ATP synthase

Carroll

Ding

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

109

106

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The opening of the permeability transition pore, a nonspecific channel in inner mitochondrial membranes, is triggered by an elevated total concentration of calcium ions in the mitochondrial matrix, leading to disruption of the inner membrane and necrotic cell death. Cyclosporin A inhibits pore opening by binding to cyclophilin D, which interacts with the pore. It has been proposed that the pore is associated with the ATP synthase complex. Previously, we confirmed an earlier observation that the pore survives in cells lacking membrane subunits ATP6 and ATP8 of ATP synthase, and in other cells lacking the enzyme’s c8rotor ring or, separately, its peripheral stalk subunits b and oligomycin sensitive conferral protein. Here, we investigated whether the pore is associated with the remaining membrane subunits of the enzyme. Individual deletion of subunits e, f, g, and 6.8-kDa proteolipid disrupts dimerization of the complex, and deletion of DAPIT (diabetes-associated protein in insulin sensitive tissue) possibly influences oligomerization of dimers, but removal of each subunit had no effect on the pore. Also, we removed together the enzyme’s membrane bound c8ring and the δ-subunit from the catalytic domain. The resulting cells assemble only a subcomplex derived from the peripheral stalk and membrane-associated proteins. Despite diminished levels of respiratory complexes, these cells generate a membrane potential to support uptake of calcium into the mitochondria, leading to pore opening, and retention of its characteristic properties. It is most unlikely that the ATP synthase, dimer or monomer, or any component, provides the permeability transition pore.

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Section: Discussionmentioning

confidence: 59%

Persistence of the permeability transition pore in human mitochondria devoid of an assembled ATP synthase

Carroll

Ding

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

109

106

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“…Further, CypD has been shown to negatively regulate F 1 /F 0 ATP synthase activity, by binding to the Oligomycin-Sensitivity Conferring Protein (OSCP) (which links the F1 portion with the lateral stalk) thereby limiting ATP coupling and energy production [38][39][40]. ATP synthase remains a reasonable candidate for the main component of the mPTP channel, making this interaction with CypD imperative [41,42]. The requirement of these processes in the diabetic kidney is highlighted by the apparent increase in glomerular structural damage observed in the Ppif −/− mice in our study.…”

Section: Discussionmentioning

confidence: 99%

Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D

et al. 2020

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Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif −/− ) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif −/− mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif −/− as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H 2 O 2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.

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“…Every year, new knowledge about the structure and regulation of this mitochondrial pore appears. Recently, new hypotheses emerged about the nature of mPTPs that form upon conformational change of ATP synthase after Ca 2+ binding [41].…”

Section: Discussionmentioning

confidence: 99%

mPTP Proteins Regulated by Streptozotocin-Induced Diabetes Mellitus Are Effectively Involved in the Processes of Maintaining Myocardial Metabolic Adaptation

Andelova

Waczulı́ková

Talian

et al. 2020

IJMS

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Mitochondrial permeability transition pores (mPTPs) have become an important topic in investigating the initiation and signaling pathways involved in cardioprotection. Experimental streptozotocin-induced diabetes mellitus (D) was shown to provide sufficient protection to the myocardium via compensatory mechanisms enabling mitochondria to produce energy under pathological conditions during the acute phase. The hypothesized involvement of mPTPs in these processes prompted us to use liquid chromatography and mass spectrometry-based proteomic analysis to investigate the effects of the acute-phase D condition on the structural and regulatory components of this multienzyme complex and the changes caused by compensation events. We detected ADT1, ATP5H, ATPA, and ATPB as the most abundant mPTP proteins. The between-group differences in protein abundance of the mPTP complex as a whole were significantly upregulated in the D group when compared with the control (C) group (p = 0.0106), but fold changes in individual protein expression levels were not significantly altered except for ATP5H, ATP5J, and KCRS. However, none of them passed the criterion of a 1.5-fold change in differential expression for biologically meaningful change. Visualization of the (dis-)similarity between the C and D groups and pairwise correlations revealed different patterns of protein interactions under the C and D conditions which may be linked to endogenous protective processes, of which beneficial effects on myocardial function were previously confirmed.

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Why F-ATP Synthase Remains a Strong Candidate as the Mitochondrial Permeability Transition Pore

Cited by 41 publications

References 45 publications

Persistence of the permeability transition pore in human mitochondria devoid of an assembled ATP synthase

Persistence of the permeability transition pore in human mitochondria devoid of an assembled ATP synthase

Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D

mPTP Proteins Regulated by Streptozotocin-Induced Diabetes Mellitus Are Effectively Involved in the Processes of Maintaining Myocardial Metabolic Adaptation

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