Proteomics reveal PTEN as a critical mediator of sustained mitochondrial dysfunction during chronic spinal cord injury

Document Type

Article

Publication Date

6-17-2026

Institution/Department

Center for Molecular Medicine

Journal Title

Experimental neurology

Abstract

Activity of the phosphatase and tensin homologue protein (PTEN) remains elevated in neurons chronically after spinal cord injury (SCI) and suppresses tissue repair. However, PTEN may also disrupt other neuronal functions not directly related to regeneration. To better understand the role of PTEN on neuronal functions in chronic SCI, neuronal-specific PTEN-KO was induced using spinal injections of retrogradely-transported AAVs (AAVrg) immediately after contusion SCI in mice. Spinal cords were harvested at 6 weeks post-injury and untargeted total proteomics was performed. Bioinformatics analyses revealed a downregulation of mitochondrial-associated proteins in chronic SCI that was reversed after PTEN-KO. We replicated the experimental conditions to validate the effects of chronic SCI ± PTEN-KO on mitochondrial functions using ex vivo respiratory testing on whole-spinal cord mitochondrial isolates. Mitochondrial respiratory capacity was reduced in chronic SCI and was restored after PTEN-KO. Next, we evaluated the extent to which chronic SCI specifically affects neuronal mitochondria and whether PGC1α upregulation can restore respiratory capacity. We designed an AAVrg vector to enable a magnetic bead pulldown approach to isolate neuron-specific mitochondria with, or without, concurrent PGC1α upregulation. AAVrg vectors were delivered into the spinal cord at 15-weeks post-injury, and neuron-specific mitochondria were isolated 6-weeks later. Neuronal mitochondria present a ~ 50% loss of respiratory capacity in chronic SCI that was restored with PGC1α upregulation. Collectively, we demonstrate that mitochondrial respiratory abilities are significantly repressed chronically after SCI, that PTEN is a major contributor to sustained mitochondrial dysfunction, and that PGC1α upregulation can restore mitochondrial bioenergetic abilities during chronic SCI. SIGNIFICANCE STATEMENT: Chronic spinal cord injury (SCI) is hallmarked by sustained motor and sensory dysfunction with little potential for repair. The chronic SCI environment limits the excitability of spared neural circuits and significantly reduces the regenerative potential of exogenously applied therapeutics. Through a series of experiments, we have derived a novel and significant observation that neuronal mitochondria exhibit a ~ 50% loss of respiratory abilities chronically after SCI in mice. Moreover, by knocking out PTEN, a protein known to be chronically hyperactive after SCI, we demonstrate the ability to restore mitochondrial respiratory abilities. Our discoveries highlight a novel and vital pathological mechanism that is sustained chronically after SCI that is mediated by neuronal PTEN activity.

First Page

115880

Link to Full Text

Share

COinS