dVGLUT Is a Mediator of Sex Differences in Dopamine Neuron Mitochondrial Function Across Aging and in a Parkinson's Disease Model
Year: 2025
Type: article
Abstract: Sex differences in Parkinson's disease (PD) offer insights into mechanisms of dopaminergic cell resilience. Female dopamine (DA) neurons are more resilient via mechanisms that remain unclear. Here, we discovered key sex and regional differences in mitochondrial generation of cytotoxic reactive oxygen species (ROS) and their implications for DA neuron resilience using the Drosophila model. While aging raised mitochondrial ROS in DA neurons of both sexes, we observed a sexually dimorphic response in the paraquat (PQ) PD model. DA neuron knockdown of the Drosophila vesicular glutamate transporter (dVGLUT) increased mitochondrial ROS only in males, leaving females protected. Cell depolarization, a physiological stressor, similarly raised mitochondrial ROS in DA neurons selectively in males following dVGLUT knockdown. We also identified dVGLUT-dependent changes in intracellular ATP in both sexes. Overall, we discovered sexually dimorphic relationships between dVGLUT, ATP synthesis, and ROS generation in DA neurons, providing a mechanistic basis for DA neuron resilience.
Source: Aging Cell
DOI: 10.1111/acel.70096
Institution: University of Pittsburgh
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
Funders: Commonwealth of Pennsylvania, Pittsburgh Foundation, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: A novel role for midbrain glutamate co-transmitting neurons in alcohol drinking and motivated behaviors, Dopamine Neuron VGLUT2 Expression in Parkinson's Disease, G5142400015, Mechanisms for Preserving Neurons in Alzheimer's Disease-Related Dementias Across Drosophila and Mouse Models, Novel roles for the circadian transcription factor NPAS2 and striatal dopamine D3 receptor signaling in diurnal fentanyl craving and relapse, Novel roles of VGLUT in sex differences in dopamine neuron vulnerability to environmental toxicant-induced neurodegeneration, Clinical and Translational Research Training in Geriatric Mental Health
OpenAlex ID: W4410348139