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Targeting Mitochondrial Fission for Neuroprotection in Diabetic Neuropathy

Drs. Stefan Strack and Yuriy Usachev Professors of Pharmacology and members of the FOEDRC recently received a new grant from the National Institutes of Health and the National Institutes of Diabetes Digestive and Kidney Disease (NIDDK) entitled “Targeting mitochondrial fission for neuroprotection in diabetic neuropathy” for a total award of $1,702,888 over four years.

The grant will support studies that will examine a new approach for treating Diabetic Nerve damage, also known as diabetic neuropathy. Presenting with chronic pain or loss of sensation, peripheral diabetic neuropathy (PDN) is a debilitating comorbidity of diabetes that affects at least half the diabetic patient population. Since only palliative treatments are available, there is an urgent need for therapies that prevent or reverse the “dying back” degeneration of sensory fibers innervating the skin. Recent evidence suggests that diabetes compromises mitochondria, the cellular powerhouse, in sensory neurons. However, the underlying mechanisms are unknown.

Mitochondrial shape is controlled by opposing fission and fusion events. Mutations in mitochondrial fusion proteins (mitofusin-2 or Opa1) cause neurological disorders that present similarly to neurological complications in diabetic patients. Specifically,  mutations in the protein mitofusin-2 result in Charcot-Marie-Tooth disease type 2A, a peripheral neuropathy characterized by primary axon degeneration, while mutations in  the protein Opa1 cause dominant optic atrophy, the most common form of hereditary blindness.

The mitochondrial fission enzyme dynamin-related protein 1 (Drp1) is activated by removal of phosphates (dephosphorylation) from a highly conserved inhibitory phosphorylation site. Two phosphatases target this site to promote mitochondrial fission, a widely expressed the Ca2+-dependent phosphatase (PP2B or calcineurin) and a neuron-specific and mitochondria-localized protein phosphatase 2A isoform (PP2A/Bb2). Their team, which also included FOEDRC member Dr. Mark Yorek,  generated a mouse knock-out (KO) of PP2A/Bb2 and found elongated mitochondria in neurons, consistent with reduced activity of Drp1.

Predicated by preliminary evidence that Bb2 KO mice are resistant to peripheral neuropathy in both type-1 and type-2 diabetes models, the grant seeks proof-of-concept evidence that Bb2 (and other, as yet undiscovered, neuron-specific Drp1 activators) could be a drug target for the treatment of PDN. The research team further proposes to investigate how diabetes causes mitochondrial fragmentation in sensory neurons and how inhibiting mitochondrial fragmentation protects peripheral axons in diabetes. Using new mouse models and innovative in vivo imaging approaches, they will test the hypothesis that dysregulation of the mitochondrial fission/fusion equilibrium contributes to the pathogenesis of diabetic neuropathy, and that inhibition of Drp1-dependent mitochondrial fission provides neuroprotection via improvement of mitochondrial metabolism, reduction of oxidative stress, modulation of mitochondrial calcium transport and enhanced regeneration of sensory axons. We anticipate that these studies will shed light on PDN etiology, suggest new therapeutic strategies, and thus help improve quality of life for a rapidly growing diabetic population. The preliminary studies for this proposal were supported by a pilot and feasibility grant to Drs. Strack and Usachev from the Fraternal Order of Eagles Diabetes Research Center.

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