bims-curels 2023-02-19 papers

Issue of 2023–02–19
two papers selected by
Cure Mito Foundation

Elife. 2023 Feb 17. pii: e75825. [Epub ahead of print]12

Iron status influences mitochondrial disease progression in Complex I-deficient mice.

C J Kelly, Reid K Couch, Vivian T Ha, Camille M Bodart, Judy Wu, Sydney Huff, Nicole T Herrel, Hyunsung D Kim, Azaad O Zimmermann, Jessica Shattuck, Yu-Chen Pan, Matt Kaeberlein, Anthony S Grillo.

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.

Keywords: biochemistry; chemical biology; medicine; mouse

DOI: https://doi.org/10.7554/eLife.75825

Hum Mol Genet. 2023 Feb 16. pii: ddad031. [Epub ahead of print]

N-Acetylcysteine and cysteamine bitartrate prevent azide-induced neuromuscular decompensation by restoring glutathione balance in two novel surf1-/- zebrafish deletion models of Leigh syndrome.

Suraiya Haroon, Heeyong Yoon, Christoph Seiler, Bruce Osei-Frimpong, Jie He, Rohini M Nair, Neal D Mathew, Leonard Burg, Melis Kose, Chavali Venkata, Vernon E Anderson, Eiko Nakamaru-Ogiso, Marni J Falk.

SURF1 deficiency (OMIM # 220110) causes Leigh syndrome (LS, OMIM # 256000), a mitochondrial disorder typified by stress-induced metabolic strokes, neurodevelopmental regression, and progressive multisystem dysfunction. Here, we describe two novel surf1-/- zebrafish knockout models generated by CRISPR/Cas9 technology. While gross larval morphology, fertility, and survival into adulthood appeared unaffected, surf1-/- mutants manifested adult-onset ocular anomalies and decreased swimming activity, and classical biochemical hallmarks of human SURF1 disease, including reduced complex IV expression and enzymatic activity and increased tissue lactate. surf1-/- larvae also demonstrated oxidative stress and stressor hypersensitivity to the complex IV inhibitor, azide, which exacerbated their complex IV deficiency, reduced supercomplex formation, and induced acute neurodegeneration typical of LS including brain death, impaired neuromuscular responses, reduced swimming activity, and absent heartrate. Remarkably, prophylactic treatment of surf1-/- larvae with either cysteamine bitartrate or N-acetylcysteine, but not other antioxidants, significantly improved animal resiliency to stressor-induced brain death, swimming and neuromuscular dysfunction, and loss of heartbeat. Mechanistic analyses demonstrated cysteamine bitartrate pretreatment did not improve complex IV deficiency, ATP deficiency, or increased tissue lactate but did reduce oxidative stress and restore glutathione balance in surf1-/- animals. Overall, two novel surf1-/- zebrafish models recapitulate the gross neurodegenerative and biochemical hallmarks of LS, including azide stressor hypersensitivity that was associated with glutathione deficiency and ameliorated by cysteamine bitartrate or N-acetylcysteine therapy.

DOI: https://doi.org/10.1093/hmg/ddad031