Iron status influences mitochondrial disease progression in Complex I-deficient mice.
C J KellyReid K CouchVivian T HaCamille M BodartJudy WuSydney HuffNicole T HerrelHyunsung D KimAzaad O ZimmermannJessica ShattuckYu-Chen PanMatt KaeberleinAnthony S GrilloPublished in: eLife (2023)
Mitochondrial dysfunction caused by aberrant Complex I assembly and reduced activity of the electron transport chain is pathogenic in many genetic and age-related diseases. Mice missing the Complex I subunit NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) are a leading mammalian model of severe mitochondrial disease that exhibit many characteristic symptoms of Leigh Syndrome including oxidative stress, neuroinflammation, brain lesions, and premature death. NDUFS4 knockout mice have decreased expression of nearly every Complex I subunit. As Complex I normally contains at least 8 iron-sulfur clusters and more than 25 iron atoms, we asked whether a deficiency of Complex I may lead to iron perturbations, thereby accelerating disease progression. Consistent with this, iron supplementation accelerates symptoms of brain degeneration in these mice, while iron restriction delays the onset of these symptoms, reduces neuroinflammation, and increases survival. NDUFS4 knockout mice display signs of iron overload in the liver including increased expression of hepcidin and show changes in iron-responsive element-regulated proteins consistent with increased cellular iron that were prevented by iron restriction. These results suggest that perturbed iron homeostasis may contribute to pathology in Leigh Syndrome and possibly other mitochondrial disorders.
Keyphrases
- iron deficiency
- oxidative stress
- traumatic brain injury
- poor prognosis
- dna damage
- adipose tissue
- binding protein
- drug delivery
- depressive symptoms
- physical activity
- metabolic syndrome
- skeletal muscle
- white matter
- sleep quality
- blood brain barrier
- protein kinase
- cancer therapy
- endoplasmic reticulum stress
- diabetic rats
- heat stress
- solar cells