Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle

Neuron. 2024 Apr 3;112(7):1117-1132.e9. doi: 10.1016/j.neuron.2023.12.020. Epub 2024 Jan 23.


Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)-derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondria-endoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming.

Keywords: Leigh syndrome; astrocytes; direct neuronal reprogramming; mitochondria; unfolded protein response.

MeSH terms

  • Astrocytes / metabolism
  • Cellular Reprogramming
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Mitochondria / metabolism
  • Mitochondrial Diseases* / metabolism
  • Neurons / physiology
  • Unfolded Protein Response


  • NDUFS4 protein, human
  • Electron Transport Complex I