Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration

  • Mitochondrion. 2025 Dec 16:87:102110. doi: 10.1016/j.mito.2025.102110.
Cunhui Pan  1 ,  Ruowei Zhu  2 ,  Xi Huang  1 ,  Haolin Duan  1 ,  Tenghui Wu  1 ,  Xiaole Wang  1 ,  Ying Ding  3 ,  Chen Chen  1 ,  Fang He  1 ,  Jing Peng  1 ,  Fei Yin  1 ,  Xiaoting Lou  4 ,  Li Yang  5
Affiliations
  • 1. Department of Pediatrics, Clinical Research Center of Children's Neurodevelopmental Disabilities of Hunan Province, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 2. Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3. Department of Neonatology, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 4. Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Laboratory Medicine Center, Department of Genetic and Genomic Medicine, Zheiiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Laboratory Medicine and Bioengineering, Hangzhou Medica College, Hnagzhou, China.
  • 5. Department of Pediatrics, Clinical Research Center of Children's Neurodevelopmental Disabilities of Hunan Province, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: [email protected].
PMID: 41412221 DOI: 10.1016/j.mito.2025.102110
Abstract

Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous FOXRED1 mutations (c.850T>C (p.C284R)/c.1054C>T (p.R352W) and c.1054C>T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD+/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. FOXRED1 mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD+/NADH imbalance. Niacin restored the NAD+/NADH ratio in vitro, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.

Keywords
Developmental and epileptic encephalopathy; FOXRED1; Mitochondrial dysfunction; Niacin; Ohtahara Syndrome.
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