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Int J Biol Sci 2024; 20(8):2860-2880. doi:10.7150/ijbs.93445 This issue Cite

Research Paper

Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation

Kristina Xiao Liang^1,2†*✉, Anbin Chen^1,3†, Atefeh Kianian¹, Cecilie Katrin Kristiansen^1,2, Tsering Yangzom¹, Jessica Furriol^1,4, Lena Elise Høyland⁵, Mathias Ziegler⁵, Torbjørn Kråkenes^1,2, Charalampos Tzoulis^1,2, Evandro Fei Fang^6,7,8, Gareth John Sullivan^{8,9,10,11*✉}, Laurence A. Bindoff^1,2*✉

1. Department of Clinical Medicine (K1), University of Bergen, Jonas Lies vei 87, P. O. Box 7804, 5021 Bergen, Norway.
2. Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Jonas Lies vei 87, P. O. Box 7804, 5021 Bergen, Norway.
3. Department of Neurosurgery, Xinhua Hospital Affiliated toShanghai Jiaotong University School of Medicine, No. 1665, Kongjiang Road, 200092 Shanghai, China.
4. Department of Medicine, Haukeland University Hospital, Jonas Lies vei 87, P. O. Box 7804, 5021 Bergen, Norway.
5. Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway.
6. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Oslo, Norway.
7. The Norwegian Centre on Healthy Ageing (NO-Age), 1478 Oslo, Norway.
8. Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, P. O. Box 1105, 0317 Oslo, Norway.
9. Institute of Immunology, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway.
10. Hybrid Technology Hub Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P. O. Box 1110, 0317 Oslo, Norway.
11. Department of Pediatric Research, Oslo University Hospital, P. O. Box 4950, 0424 Oslo, Norway.
†These authors contributed equally to this work as first authors.
*These authors contributed equally to this work as corresponding authors.

✉ Corresponding authors: Kristina Xiao Liang, Department of Clinical Medicine (K1), University of Bergen, Jonas Lies vei 87, P. O. Box 7804, 5021 Bergen, Norway. Fax: +47 559 75165; Email: Xiao.Liangno. Laurence A. Bindoff, Department of Clinical Medicine (K1), University of Bergen, Jonas Lies vei 87, P. O. Box 7804, 5021 Bergen, Norway. Email: Laurence.Bindoffno. Gareth John Sullivan, Department of Pediatric Research, Oslo University Hospital, P. O. Box 4950, Nydalen, 0424 Oslo, Norway. Email: gareth.sullivanuio.no. More

Abstract

Mitochondrial diseases are associated with neuronal death and mtDNA depletion. Astrocytes respond to injury or stimuli and damage to the central nervous system. Neurodegeneration can cause astrocytes to activate and acquire toxic functions that induce neuronal death. However, astrocyte activation and its impact on neuronal homeostasis in mitochondrial disease remain to be explored. Using patient cells carrying POLG mutations, we generated iPSCs and then differentiated these into astrocytes. POLG astrocytes exhibited mitochondrial dysfunction including loss of mitochondrial membrane potential, energy failure, loss of complex I and IV, disturbed NAD⁺/NADH metabolism, and mtDNA depletion. Further, POLG derived astrocytes presented an A1-like reactive phenotype with increased proliferation, invasion, upregulation of pathways involved in response to stimulus, immune system process, cell proliferation and cell killing. Under direct and indirect co-culture with neurons, POLG astrocytes manifested a toxic effect leading to the death of neurons. We demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astrocytes. These findings reveal a novel role for dysfunctional astrocytes that contribute to the pathogenesis of POLG diseases.

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