Infection driven inflammation as a novel driver of neurodegeneration in mitochondrial disease

Primary mitochondrial diseases (PMDs) are the most common inborn errors of metabolism, affecting ~1 in 5,000 births with devastating neurologic manifestations. A hallmark clinical feature of PMD is infection-triggered permanent neurologic deterioration, where intercurrent infections precipitate acute worsening of neurologic function without return to baseline after infection resolution. This distinctive pattern provides a compelling model to investigate fundamental mechanisms underlying post-infectious neurologic sequelae applicable to other infection-associated chronic neurologic illnesses and post-viral fatigue syndromes. Emerging preclinical and patient data support a central role for the immune system in the progression of PMD. Based on these emerging data, we propose that infections causally accelerate neurodegeneration in PMD through immune cell intrinsic mitochondrial dysfunction that results in dysfunctional immunity, and that different genetic causes of PMD lead to distinct patterns of immune alterations that actively contribute to the severity and phenotype of post-infectious neurologic deterioration. We aim to define the spectrum of immune dysfunction across diverse genetic forms of human PMD through comprehensive immunophenotyping and functional assessment using single-cell RNA sequencing and cytokine profiling of patient peripheral blood mononuclear cells at baseline and post-stimulation. Further, moving beyond correlation, we will determine if mitochondrial dysfunction in immune cells causally accelerates neurodegeneration using the NDUFS4 knockout mouse model of PMD. Specifically by investigating whether influenza infection drives neurologic decline and leveraging genetic restoration of mitochondrial function specifically in immune cells to establish causality. This work will integrate translational pipelines including single- cell sequencing with novel animal models to causally define the mechanisms linking mitochondrial dysfunction, immune dysregulation, and post-infectious neurologic deterioration. Importantly, This research directly addresses NINDS priorities by investigating mechanisms of mitochondrial dysfunction contributing to nervous system dysfunction in infection-associated chronic illnesses, providing insights into shared pathways across multiple post-infectious neurologic conditions and identifying potential therapeutic targets for these disorders. Project Number: 1R21NS149367-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Samuel Weinberg | Institution: NORTHWESTERN UNIVERSITY, CHICAGO, IL | Award Amount: $214,329 | Activity Code: R21 | Study Section: Neural Oxidative Metabolism and Death Study Section[NOMD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11356275