PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death
Year: 2026
Type: preprint
Abstract: Genetic loss of the mitochondrial control enzyme PINK1 leads to Parkinson's disease, characterized by dopaminergic neuron degeneration and neuroinflammation, yet its role in glia remains poorly understood. To address this gap, we investigated how the function of astrocytes and their ability to support neurons is influenced by PINK1 deficiency. For the first time, we demonstrate that human astrocytes exhibit robust PINK1 activity. Next, the first bulk transcriptomic study of human PINK1 mutant astrocytes was performed followed by biochemical validation at the protein level, uncovering homeostatic collapse. Co-culture experiments demonstrated that this astrocyte dysfunction drives neuronal damage through non-cell-autonomous mechanisms. Notably, pharmacological enhancement of autophagy successfully mitigated this inflammatory secretome, indicating that mitochondrial quality control deficits are reversible. These findings establish an unexpected role for PINK1 in glial biology, reveal that astrocytes are vulnerable to mitophagy deficits, and highlight a novel mechanistic link connecting mitochondrial dysfunction, neuroinflammation, and neurodegeneration.
Institutions: Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Mitochondrial Sirtuin 3 in Parkinson's disease, Molecular mechanisms of PINK1-PRKN directed mitochondrial quality control, The Mayo Clinic IMSD: Developing scientists through disease-relevant research, Resolving the Critical Role of PINK1 Expression and Activity in Parkinson's Disease Pathophysiology and Therapeutic Intervention, Synergistic Interaction of amyloid-beta and alpha-synuclein in Lewy body Dementia, Selective autophagy in Alzheimer's disease and related dementias, Elucidating the Pathomechanisms of APOE4 in Lewy Body Dementia
OpenAlex ID: W7164007436