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 peripheral axons in PDN. Recent evidence suggests that diabetes compromises mitochondrial structure and function in sensory neurons. However, the underlying mechanisms are unknown. Mitochondrial shape is controlled by opposing fission and fusion events. Mutations in mitochondrial fusion enzymes cause neurological disorders that present similarly to neurological complications in diabetic patients. Specifically, mitofusin-2 mutations result in Charcot-Marie-Tooth disease type 2A, a peripheral neuropathy characterized by primary axon degeneration, while mutations in Opa1 cause dominant optic atrophy, the most common form of hereditary blindness. The mitochondrial fission enzyme dynamin-related protein 1 (Drp1) is activated by dephosphorylation of a highly conserved inhibitory PKA phosphorylation site. Two phosphatases target this site to promote mitochondrial fission, the Ca2+-dependent phosphatase calcineurin and a neuron-specific and mitochondria- localized isoform of protein phosphatase 2A containing the B?2 regulatory subunit (PP2A/B?2). We generated a mouse knock-out (KO) of B?2 and found elongated mitochondria in neurons, consistent with deletion of a Drp1 activator. B?2 KO results in a striking reduction in infarct volume following ischemic stroke, indicating that mitochondrial elongation is neuroprotective. Conversely, knocking out A Kinase Anchoring Protein 1 (AKAP1), the protein that recruits PKA to the outer mitochondrial membrane to maintain Drp1 in a phosphorylated and inhibited state, causes mitochondrial fragmentation and exacerbates stroke injury. Supported by preliminary evidence that B?2 KO mice are resistant to peripheral neuropathy in both type-1 and type-2 diabetes models, the present proposal seeks proof-of-concept evidence for B?2 (and other, as yet undiscovered, neuron-specific Drp1 activators) as a drug target for the treatment of PDN. We further propose 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, we will test the overarching 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 ROS, modulation of mitochondrial Ca2+ 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.

Public Health Relevance

With more than a third of the US population considered obese, peripheral diabetic neuropathy, a common and debilitating neurological complication of diabetes, has tremendous and rising socioeconomic impact. This proposal examines how diabetes affects the structure and function of mitochondria in nerve cells and test the idea that preventing mitochondrial failure in nerve cells can restore nerve function in diabetes. Our results may lead to new treatments for peripheral diabetic neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK116624-02
Application #
9698345
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jones, Teresa L Z
Project Start
2018-06-01
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242