The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.

Abstract

BACKGROUND: Metabolic dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), emerging early and strongly associated with disease progression and prognosis. While systemic hypermetabolism is well documented, the central mechanisms underlying energy imbalance remain poorly understood. The hypothalamus, a key regulator of whole-body energy homeostasis, has recently been implicated in ALS, but its mechanistic contribution to metabolic failure and disease progression remains unclear. METHODS: We analyzed the hypothalamus SOD1-G93A mouse model using proteomics (ProteomeXchange ID: PXD070931), mitochondrial bioenergetic assays, immunofluorescence, flow cytometry, and gene expression to assess hypothalamic mitochondrial function, glial activation, and melanocortin system integrity. Limited analyses in the hFUS model confirmed the presence of key hypothalamic alterations, supporting a shared vulnerability across ALS models. In SOD1-G93A mice, the metabolic modulator trimetazidine (TMZ) was administered presymptomatically to evaluate effects on hypothalamic pathology, metabolic regulation, disease onset, and survival. FINDINGS: We provide the first evidence that mitochondrial bioenergetic defects arise specifically in the hypothalamus of ALS models before symptom onset. Proteomic profiling revealed dysregulation of mitochondrial pathways, while functional assays confirmed impaired bioenergetics in the hypothalamus. These deficits were accompanied by local pro-inflammatory activation of astrocytes and microglia, mitochondrial dysfunction in glial cells, and early disruption of the arcuate nucleus melanocortin system. Limited analyses in hFUS mice confirmed selective hypothalamic vulnerability. Early TMZ treatment in SOD1-G93A mice specifically restored hypothalamic bioenergetics, normalized local glial activation and melanocortin signaling, delayed disease onset, and extended survival. INTERPRETATION: These findings establish the hypothalamus as an early and selectively vulnerable site in ALS, where region-specific mitochondrial dysfunction contributes to metabolic and neuroinflammatory alterations. Targeting hypothalamic bioenergetics represents a promising therapeutic strategy.