Hexosamine Pathway as a Therapeutic Strategy in Primary Mitochondrial Encephalopathy

The central nervous system (CNS) has an extraordinarily high energetic demand and consumes around 20% of whole-body resting oxygen consumption, while accounting for merely ~2% of body mass. As a result, it is not surprising that CNS cells (neurons, astrocytes, microglia, etc.) are well equipped with great mitochondrial content to support many of the energy-consuming cellular processes, including synapses, axonal branching and transport, membrane potential polarization, ion transport, and others [1]. Unfortunately, the great reliance on mitochondrial bioenergetics comes with a wide number of primary mitochondrial neurological syndromes, such as mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), Leigh syndrome, Chronic progressive external ophthalmoplegia (CPEO), and others [2]. In addition to primary mitochondrial neurological syndromes, common late-onset brain diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, can also involve mitochondrial mutations [3]. The evidence ranges from pure bioenergetics defects to mitochondrial quality control, retrograde signaling, calcium buffering capacity, and redox homeostasis. In this issue of Acta Physiologica, Jiménez-Sánchez et al. [4]. investigated the development of a primary mitochondrial fatal encephalopathy using a mouse model with a mutation in Coq9, the enzyme responsible for the biosynthesis of the coenzyme Q (Q10) (Figure 1a). The study addresses a series of provocative questions with broad-spectrum implications. For instance, what is the temporal relationship between cellular changes and symptoms? What are the main structural and cellular organizations affected by mitochondrial dysfunction? Is there a hierarchical set of components more susceptible to failure in such conditions? Answering these questions is fundamental to establishing causality as well as to improving treatment for patients suffering from primary mitochondrial neurological syndromes. The authors provide a detailed timeline of pathological events, demonstrating that neuronal loss in the cortex, myelin damage, and astrocyte activation in the brainstem occur early (ca. 1 month of age) in this model, and precede the onset of motor symptoms. Interestingly, microglial activation appeared in late stages of neurological impairment, clarifying the cellular cascade initiated by this specific genetic defect (Figure 1a). Based on these findings, it could be informative to dissect cell-type composition during the progression of the neurodegeneration. For example, by co-staining NF-kB p65 with GFAP and Iba1 in the cortex and brainstem to quantify nuclear localization per cell type. This approach would provide per-cell pathway activation and partially control for compositional effects in aggregate measurements. The mitochondrial dysfunction model used by Jiménez-Sánchez et al. [4]. carries a pathogenic variant of the Coq9 mutation (Coq9R239X). Coq9 is a nuclear-encoded mitochondrial protein involved in ubiquinone (CoQ) biosynthesis, where Coq9R239X mice display severely low CoQ levels. CoQ plays a fundamental role in the electron transport chain (ETC) activity, being involved in electron transfer to support energy production. Moreover, within ETC, CoQ affects the redox pressure of mitochondrial respiratory complexes as well as substrate oxidation. However, given the involvement of CoQ as an intermediate electron acceptor within ETC, impairment of its function also reverberates to the redox balance and metabolism. Therefore, CoQ sits at the intersection of mitochondrial bioenergetic efficiency and cellular metabolic control. Interestingly, Jimenez-Sanchez noted abnormally low levels of N-acetylglucosamine (GlcNAc) in the brains of Coq9R239X mice, suggesting that impaired CoQ synthesis affects hexosamine homeostasis. GlcNAc is a dynamic nutrient sensor, bridging the metabolic status of cells with quality control of protein folding, trafficking, and degradation. Therefore, glycosylation imbalance could disrupt several fundamental cellular processes. In fact, abnormal levels of GlcNAc and cycling enzymes, such as O-GlcNAc transferase and O-GlcNAcase, are associated with neurodegenerative diseases (i.e., Alzheimer's, Parkinson's, ALS, and others), aging, and some types of cancer [5, 6]. Although previous research has exploited GlcNAc metabolism as a therapeutic strategy for neuroinflammation and multiple cognition-impairment diseases, this study is the first to test its efficacy in a genetic model of primary mitochondrial dysfunction associated with CoQ deficiency. GlcNAc supplementation ameliorated behavioral deficits and attenuated inflammatory status in Coq9R239X mice without impacting overall survival rate or myelination (Figure 1b). These findings suggest primary mitochondrial neurodisorders can be treated without altering the core of bioenergetic failure. The current approach shifts the application of GlcNAc from autoimmune and/or secondary neurodegeneration to a disease caused primarily by a metabolic deficiency of mitochondrial etiology. Given the broad cellular and systemic implications of rescuing GlcNAc levels [7], it will be interesting to map the protein landscape of post-translational modifications and protein quality control following GlcNAc treatment to test whether GlcNAc supplementation corrects a primary metabolic defect or buffers the inflammatory cascade. An open question remains: How does CoQ deficiency mechanistically impact GlcNAc levels? Given the broad cellular effects of mitochondrial dysfunction, it is plausible to speculate that the hexosamide pathway is affected by redox-driven metabolic rerouting, impaired mitochondrial retrograde signaling, or an imbalance of glycolytic intermediates. Testing these hypotheses in the future will help to establish whether hexosamine dysregulation is causal or compensatory in primary mitochondrial neurological syndromes. The work from Jiménez-Sánchez reveals that cellular alterations often precede the onset of clinical symptoms, with inflammation emerging as a downstream response to early mitochondrial disturbances. Because mitochondria regulate a broad spectrum of cellular processes, it remains unanswered how CoQ deficiency affects hexosamine metabolism. Nevertheless, GlcNAc treatment appears to restore aspects of cellular function through modulation of inflammatory status, highlighting a common therapeutic target even in neurological disorders linked to primary mitochondrial impairment. The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.