The Role of CLUH in Maintaining Mitochondrial Function in Motoneuronal Axons

Aims: The aim of this study is to investigate the role of CLUH (Clustered mitochondria homolog) in maintaining mitochondrial function and translation within motoneuronal axons to prevent peripheral neuropathy.

Methods: Researchers employed genetically modified mouse models lacking CLUH expression specifically in motoneuronal axons. Axonal mitochondria were assessed using transmission electron microscopy to evaluate morphology and density. Immunofluorescence staining and confocal microscopy were utilized to examine mitochondrial membrane potential and oxidative stress markers. Additionally, RNA sequencing and quantitative PCR were conducted to analyse the impact of CLUH deficiency on axonal mRNA levels and protein translation machinery.

Results: The study revealed that CLUH-deficient motoneuronal axons exhibited significant alterations in mitochondrial morphology, characterized by fragmented and swollen mitochondria compared to control axons. Functional assays demonstrated impaired mitochondrial membrane potential and dysregulated axonal protein synthesis machinery in CLUH-deficient motor axons. These molecular and functional deficits correlated with signs of neuropathic dysfunction in motoneuron-CLUH-deficient mice, including decreased axonal transport efficiency and compromised neuromuscular junction integrity.

Conclusions: CLUH is essential for maintaining axonal health by ensuring proper mitochondrial function and translation, thereby preventing peripheral neuropathy.

Comments. The authors of this well-designed research provided compelling evidence that the absence of CLUH in motor nerve fibers results in impaired mitochondrial health and disrupted protein synthesis machinery, contributing to symptoms of motor neuropathy. Nonetheless, the focus of this study on CLUH in motor neurons raises an interesting question about whether CLUH plays a similar protective role in sensory neurons. Furthermore, the study primarily relied on animal models, which may not fully mirror the complexities of human neuropathies. Hence, further investigations are necessary to confirm the translational relevance in human clinical settings. Overall, this study provides valuable insights into how the CLUH protein protects the integrity of motor nerve fibers in peripheral neuropathy and highlights potential treatment therapeutic avenues that rescues mitochondrial function and protein synthesis pathways in neurons to preserve axonal health.

Ali Jaafar

Reference. Zaninello M, Schlegel T, Nolte H, Pirzada M, Savino E, Barth E, Klein I, Wüstenberg H, Uddin T, Wolff L, Wirth B, Lehmann HC, Cioni JM, Langer T, Rugarli EI. CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy. Sci Adv. 2024 May 31;10(22):eadn2050. doi: 10.1126/sciadv.adn2050. Epub 2024 May 29. PMID: 38809982; PMCID: PMC11135423

https://www.science.org/doi/10.1126/sciadv.adn2050