Whilst the link between primary mitochondrial defects and disease is clear, multiple lines of evidence link mitochondrial dysfunction and neurodegeneration so that no one mechanism prevails. This suggests that either mitochondrial dysfunction is a “common” final pathway for all forms of neurodegeneration, or that mitochondrial promiscuity, i.e. their involvement in almost any cellular process, means that these changes are secondary, and are either not involved in the disease process or only partly so.

The group has established a robust model system to investigate disease related changes in mitochondrial function. Reprogramming patient fibroblasts to induced pluripotent stem cells (iPSC) provides a substrate from which any cell type/tissue can be generated. For example, the group has generated neuronal lineages including dopaminergic neurones, motor neurones, glial cells such as astrocytes and oligodendrocytes and mesenchymal cells such as cardiomyocytes. MMN’s role in Neuro-SysMed is to provide this expertise in generating stem cell models in appropriate cell lineages (e.g. neuronal or glial). MNN is now extending its work into generating complex structures called organoids. The group has successfully generated cortical organoids (“brains in dish”) from patients with mitochondrial disease and controls.

The group’s studies with stem cell models show that it is possible to replicate findings such as respiratory chain complex I deficiency and mtDNA depletion in neural stem cells (NSC), progenitors committed to the neuronal lineage, but with retained ability to divide. The group published their findings in NSC with POLG mutations in EMBO Molecular Medicine. They have also submitted work showing that astrocytes from POLG patients also manifest a phenotype, but more interestingly, they become toxic for neurones. Astrocyte involvement in neurodegeneration is an exciting new area and these groundbreaking findings suggest that mitochondrial dysfunction may be a common stimulus driving astrocyte conversion from normal to the toxic A1 type that damage and potentially kills neurones. This work is under review. Lastly, the group has been looking at various candidate compounds for treating mitochondrial dysfunction. They found that N-acetylcysteine amide was able to reduce oxidative stress and improve mitochondrial function in iPSC derived dopaminergic neurones. This was published in Experimental Neurology.

The MMN group has also generated cardiomyocytes from iPSC and done this in a 96 well format. This method was published in Scientific Reports. The importance of this work is that it confirms our ability to generate a wide range of differentiated cell types, something that can be important in the future.

The group’s recent clinical work has focussed on greater understanding of POLG related disease and the elaboration of biomarkers with which to diagnose and follow mitochondrial diseases. studies of POLG related disease have used the POLG registry that now contains >180 patients, both living and dead. This unique material has allowed them to generate a simplified classification of POLG related disease, to investigate the impact of gender and pregnancy on disease course and outcome, and to study mental health and quality of life in affected individuals. Intriguingly, they found clear gender differences: males tended to present and die earlier than females and onset and worsening in females was associated with onset of menarche and pregnancy.

The search for biomarkers has focussed on two areas: novel mitochondrial disease markers and studies to investigate how best to use known biomarkers. Neurofilament light chain (NF-L) released by damage to neurones has been used as a marker to follow disease progression in multiple sclerosis. The group asked the question whether it could be useful also in mitochondrial disease, and performed a study comparing it with other known mitochondrial biomarkers, namely FGF21 and GDF15. In their pilot study, they showed that NF-L could be useful in detecting central nervous system involvement in patients with systemic mitochondrial disease. In those with disease restricted to skeletal muscle, FGF21 and GDF15 were more sensitive. They also investigated the detection of mtDNA deletions and showed that urine sediment cells were an appropriate source of DNA, thus obviating the need for muscle biopsy in these patients.

Selected Key Publications

1. Hytönen MK, Sarviaho R, Jackson CB, Syrjä P, Jokinen T, Matiasek K, Rosati M, Quintero I, Arumilli M, Donner J, Anttila M, Bindoff LA, Suomalainen A, Lohi H. In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration. Hum Genet. Under review. This work is a follow up on the human studies performed with Professor Zeviani (Padua) and confirms that mitochondria are involved in amyloid beta metabolism.
2. Liang KX, Vatne GH, Kristiansen CK, Levglevskyi O, Kondratskaya E, Glover JC, Chen A, Sullivan GJ, Bindoff LA. N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation. Exp Neurol. 2020 Nov 29;337:113536. doi: 10.1016/j.expneurol.2020.113536.
3. Balafkan N, Mostafavi S, Schubert M, Siller R, Liang KX, Sullivan G, Bindoff LA. A method for differentiating human induced pluripotent stem cells toward functional cardiomyocytes in 96-well microplates. Sci Reports, 2020 28;10(1):18498. doi: 10.1038/s41598-020-73656-2.
4. Liang KX, Kristiansen CK, Mostafavi S, Vatne GH, Zantingh GA, Kianian A, Tzoulis C, Høyland LE, Ziegler M, Perez RM, Furriol J, Zhang Z, Balafkan N, Hong Y, Siller R, Sullivan GJ, Bindoff LA. Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations. EMBO Mol Med 2020 Oct 7;12(10):e12146. doi: 10.15252/emmm.202012146.
5. Lehtonen JM, Auranen M, Darin N, Sofou K, Bindoff LA, Hikmat O, Uusimaa J, Vieira P, Tulinius M, Lönnqvist T, de Coo IF, Suomalainen A, Isohanni P. Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease. J Inherit Metab Dis. 2020 Aug 28. doi: 10.1002/jimd.1
6. Varhaug, KN, Nido,GS, de Coo I, Isohanni P, Suomalainen A, Tzoulis C, Knappskog P, Bindoff LA. Using urine to diagnose large-scale mtDNA deletions in adult patients. Ann Clin Transl Neurol. 2020 Aug;7(8):1318-1326. doi: 10.1002/acn3.51119.
7. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CM, Brodtkorb E, Ostergaard E, de Coo IFM, PiasPeleteiro L, Isohanni P, Uusimaa J, Darin N, Rahman S, Bindoff LA. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020 Jul;43(4):726-736. doi: 10.1002/jimd.12211.
8. Liang X, Kristiansen, CK, Vatne GH, Hong Y, Bindoff LA. Patient-specific neural progenitor cells derived from induced pluripotent stem cells offer a promise of good models for mitochondrial disease. Cell Tissue Res. 2020 Apr;380(1):15-30.

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