# Targeting Mitochondrial Fission for Neuroprotection in Diabetic Neuropathy

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $419,630

## Abstract

Project Summary / Abstract
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 Bβ2 regulatory subunit (PP2A/Bβ2). We generated
a mouse knock-out (KO) of Bβ2 and found elongated mitochondria in neurons, consistent with deletion of a
Drp1 activator. Bβ2 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 Bβ2 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 Bβ2 (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 strat...

## Key facts

- **NIH application ID:** 9925077
- **Project number:** 5R01DK116624-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** STEFAN STRACK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,630
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925077

## Citation

> US National Institutes of Health, RePORTER application 9925077, Targeting Mitochondrial Fission for Neuroprotection in Diabetic Neuropathy (5R01DK116624-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9925077. Licensed CC0.

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