High Dietary Fat Consumption Impairs Axonal Mitochondrial Function In Vivo

Area of Science:

• Neuroscience
• Metabolic Disorders
• Mitochondrial Biology

Background:

• Peripheral neuropathy (PN) is a common complication of prediabetes and type 2 diabetes (T2D).
• PN pathogenesis in T2D and prediabetes is linked to dyslipidemia, but molecular mechanisms remain unclear.
• Sensory neurons depend on axonal mitochondria for energy; dyslipidemia can cause mitochondrial dysfunction.

Purpose of the Study:

• To investigate the effects of diet-induced dyslipidemia on mitochondrial function and dynamics in sensory axons.
• To identify *in vivo* mitochondrial alterations correlating with prediabetic peripheral neuropathy.

Main Methods:

• Utilized a high-fat diet (HFD)-fed murine model of prediabetes.
• Evaluated mitochondrial membrane potential (MMP), axonal impulse conduction, and Ca2+ levels in saphenous nerve sensory axons.
• Assessed mitochondrial morphology and PGC1α expression.

Main Results:

• HFD decreased axonal mitochondrial membrane potential (MMP) and impaired nerve impulse conduction.
• HFD-induced mitochondria showed reduced MMP dissipation in response to increased energy demand, indicating loss of reserve capacity.
• HFD decreased axonal Ca2+ levels and increased mitochondrial lengthening and PGC1α expression.

Conclusions:

• Mitochondrial dysfunction contributes to axonal energy and Ca2+ imbalance in prediabetic PN.
• Impaired mitochondrial function and altered axonal energy homeostasis are early pathogenic events in PN.
• Findings provide insights into PN mechanisms associated with prediabetes and dyslipidemia *in vivo*.