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Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity.

ABSTRACT: Cardiolipin (CL) is an anionic phospholipid at the inner mitochondrial membrane (IMM) that facilitates the formation of transient non-bilayer (non-lamellar) structures to maintain mitochondrial integrity. CL modulates mitochondrial functions including ATP synthesis. However, the biophysical mechanisms by which CL generates non-lamellar structures and the extent to which these structures contribute to ATP synthesis remain unknown. We hypothesized that CL and ATP synthase facilitate the formation of non-bilayer structures at the IMM to stimulate ATP synthesis. By using 1H NMR and 31P NMR techniques, we observed that increasing the temperature (8°C to 37°C), lowering the pH (3.0), or incubating intact mitochondria with CTII - an IMM-targeted toxin that increases the formation of immobilized non-bilayer structures - elevated the formation of non-bilayer structures to stimulate ATP synthesis. The F0 sector of the ATP synthase complex can facilitate the formation of non-bilayer structures as incubating model membranes enriched with IMM-specific phospholipids with exogenous DCCD-binding protein of the F0 sector (DCCD-BPF) elevated the formation of immobilized non-bilayer structures to a similar manner as CTII. Native PAGE assays revealed that CL, but not other anionic phospholipids, specifically binds to DCCD-BPF to promote the formation of stable lipid-protein complexes. Mechanistically, molecular docking studies identified two lipid binding sites for CL in DCCD-BPF. We propose a new model of ATP synthase regulation in which CL mediates the formation of non-bilayer structures that serve to cluster protons and ATP synthase complexes as a mechanism to enhance proton translocation to the F0 sector, and thereby increase ATP synthesis.

SUBMITTER: Gasanov SE

PROVIDER: S-EPMC5755587 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity.

Gasanov Sardar E SE Kim Aleksandr A AA Yaguzhinsky Lev S LS Dagda Ruben K RK

Biochimica et biophysica acta. Biomembranes 20171124 2

Cardiolipin (CL) is an anionic phospholipid at the inner mitochondrial membrane (IMM) that facilitates the formation of transient non-bilayer (non-lamellar) structures to maintain mitochondrial integrity. CL modulates mitochondrial functions including ATP synthesis. However, the biophysical mechanisms by which CL generates non-lamellar structures and the extent to which these structures contribute to ATP synthesis remain unknown. We hypothesized that CL and ATP synthase facilitate the formation ...[more]

PMID: 29179995

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Project description:New findingsWhat is the central question of this study? Humans with obesity have lower ATP synthesis in muscle along with lower content of the ?-subunit of the ATP synthase (?-F1-ATPase), the catalytic component of the ATP synthase. Does lower synthesis rate of ?-F1-ATPase in muscle contribute to these responses in humans with obesity? What is the main finding and its importance? Humans with obesity have a lower synthesis rate of ?-F1 -ATPase and ATP synthase specific activity in muscle. These findings indicate that reduced production of subunits forming the ATP synthase in muscle may contribute to impaired generation of ATP in obesity.AbstractThe content of the ?-subunit of the ATP synthase (?-F1 -ATPase), which forms the catalytic site of the enzyme ATP synthase, is reduced in muscle of obese humans, along with a reduced capacity for ATP synthesis. We studied 18 young (37 ± 8 years) subjects of which nine were lean (BMI = 23 ± 2 kg m-2 ) and nine were obese (BMI = 34 ± 3 kg m-2 ) to determine the fractional synthesis rate (FSR) and gene expression of ?-F1 -ATPase, as well as the specific activity of the ATP synthase. FSR of ?-F1 -ATPase was determined using a combination of isotope tracer infusion and muscle biopsies. Gene expression of ?-F1 -ATPase and specific activity of the ATP synthase were determined in the muscle biopsies. When compared to lean, obese subjects had lower muscle ?-F1 -ATPase FSR (0.10 ± 0.05 vs. 0.06 ± 0.03% h-1 ; P < 0.05) and protein expression (P < 0.05), but not mRNA expression (P > 0.05). Across subjects, abundance of ?-F1 -ATPase correlated with the FSR of ?-F1 -ATPase (P < 0.05). The specific activity of muscle ATP synthase was lower in obese compared to lean subjects (0.035 ± 0.004 vs. 0.042 ± 0.007 arbitrary units; P < 0.05), but this difference was not significant after the activity of the ATP synthase was adjusted to the ?-F1 -ATPase content (P > 0.05). Obesity impairs the synthesis of ?-F1 -ATPase in muscle at the translational level, reducing the content of ?-F1 -ATPase in parallel with reduced capacity for ATP generation via the ATP synthase complex.

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Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity.

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Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity.

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