Mitochondrial transplantation ameliorates experimental autoimmune encephalomyelitis by modulating the Th17/Treg balance and restoring metabolic homeostasis

TL;DR

Mitochondrial transplantation reduces symptoms of a mouse model of multiple sclerosis by improving immune balance and restoring cell energy.

Contribution

This study demonstrates that mitochondrial transplantation can modulate immune responses and restore metabolic function in experimental autoimmune encephalomyelitis.

Findings

Mitochondrial transplantation reduced EAE severity, inflammation, demyelination, and fibrosis in mice.

Treated mice showed increased Treg cells, reduced Th17 cells, and improved mitochondrial biogenesis.

Human PBMCs co-cultured with mitochondria showed enhanced ATP production and suppressed ROS.

Abstract

Mitochondrial dysfunction has been increasingly implicated in the pathogenesis of multiple sclerosis (MS), contributing to oxidative stress, immune dysregulation, and neurodegeneration. Current therapies primarily target inflammation but do not adequately address mitochondrial impairment or progressive tissue damage. This study aimed to evaluate the therapeutic potential of mitochondrial transplantation in experimental autoimmune encephalomyelitis (EAE), a murine model of MS, by investigating its effects on immune modulation, mitochondrial function, and tissue integrity.

EAE was induced in mice using myelin oligodendrocyte glycoprotein. Isolated mitochondria were administered intravenously, and clinical progression, spinal cord histology, immune cell populations, mitochondrial activity, fibrosis, and gut microbiota composition were assessed. Additionally, human peripheral blood mononuclear cells (PBMCs) from MS patients were co-cultured with mitochondria to examine ATP production, reactive oxygen species levels, and T cell differentiation.

Mitochondrial transplantation significantly reduced EAE severity, spinal cord inflammation, demyelination, and fibrosis. Treated mice showed increased regulatory T (Treg) cells, reduced T helper 17 (Th17) cells, improved mitochondrial biogenesis, and decreased oxidative stress. Gut microbiome analysis revealed beneficial compositional changes. In human PBMCs, mitochondrial transfer enhanced ATP synthesis, suppressed mitochondrial ROS, and promoted Treg differentiation while inhibiting pro-inflammatory cytokines.

Our findings suggest that mitochondrial transplantation restores mitochondrial function, rebalances immune responses, and mitigates neuroinflammation and fibrosis in EAE. This approach offers a novel therapeutic strategy for MS by addressing both metabolic and immunological drivers of disease progression.

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