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F1F0 ATP Synthase–Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline
- Source :
- Diabetes
- Publication Year :
- 2016
- Publisher :
- American Diabetes Association, 2016.
-
Abstract
- Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif −/−) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca2+ overload. Diabetes-induced elevation of CypD triggers enhancement of F1F0 ATP synthase–CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F1F0 ATP synthase–CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Long-Term Potentiation
Mitochondrion
Biology
medicine.disease_cause
Pathophysiology
Diabetes Mellitus, Experimental
Cyclophilins
Mice
03 medical and health sciences
chemistry.chemical_compound
Cognition
Internal medicine
Internal Medicine
medicine
Animals
Humans
Cognitive Dysfunction
Cognitive decline
Mice, Knockout
ATP synthase
MPTP
PPIF
Mitochondrial Proton-Translocating ATPases
Mitochondria
3. Good health
030104 developmental biology
Endocrinology
chemistry
Mitochondrial permeability transition pore
Anesthesia
Synapses
Synaptic plasticity
biology.protein
Cognition Disorders
Reactive Oxygen Species
Cyclophilin D
Oxidative stress
Protein Binding
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 65
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....ba10a842c21274eb260bac34a8dd464d