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. 2021 Jan 4;141(2):257–279. doi: 10.1007/s00401-020-02252-5

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — C9orf72-dependent dysfunctional axonal homeostasis is caused by mitochondrial bioenergetic dysfunction in human iPSC-derived MNs. a–c Mean fold change ± SEM of gene expression normalised to the respective isogenic control (or control) determined via RT-PCR; genotypes used: two independent controls [Con-1, Con-2], three independent patient-derived C9orf72 lines [C9-1, C9-2, C9-3; red bars] with their corresponding isogenic controls [C9-1Δ, C9-2Δ, C9-3Δ; blue bars], with (hatched bars) and without (unhatched bars) PGC1α overexpression, for transcripts: MT-ND4 (complex I; a), MT-CO3 (complex IV; b), and MT-ATP6 (complex V; c). d Quantification of the axonal mitochondrial number in a 100 µm stretch of distal axon in C9orf72-MNs and their respective isogenic controls, with (hatched bars) and without (unhatched bars) PGC1α overexpression. Data are represented as mean ± SEM; n ≥ 4 axons per line per experiment, with experiments repeated in three independent cultures from different differentiations (N = 3). Statistical significance was evaluated with one-way ANOVA with post hoc mutant-isogene paired FDR-corrected t tests. Quantification of the relative oxygen consumption rate (OCR) as measured by the Seahorse Analyzer, normalised to the amount of total protein, denoting basal (e) and maximal FCCP-uncoupled (f) mitochondrial respiration for C9orf72-MNs and isogenic paired controls, with (hatched bars) and without (unhatched bars) PGC1α overexpression. Data are represented as mean fold change (relative to C9orf72-ALS) ± SEM; n ≥ 4 wells per line per experiment, with experiments repeated in three independent cultures from different differentiations (N = 3). Statistical significance was evaluated with one-way ANOVA with post hoc mutant-isogene paired FDR-corrected t tests. g Quantification of the SMI-312 antibody-labelled axonal length in MNs 7 days post platedown, with (hatched bars) and without (unhatched bars) PGC1α overexpression (n > 15 axons per independent MN differentiation, N = 3 independent differentiations; data are represented as mean ± SEM; genotypes used: three independent patient-derived C9orf72 lines [C9-1, C9-2, C9-3] with their corresponding isogenic controls [C9-1Δ, C9-2Δ, C9-3Δ]; statistical significance was evaluated using the Kruskal–Wallis test with FDR correction). h Quantification of the percentage of motile mitochondria (labelled with mitoDsRed2) relative to the total number of mitochondria in a 100 µm stretch of axon in C9orf72-MNs, with (hatched bars) and without (unhatched bars) PGC1α overexpression, and isogenic paired controls; two independent healthy controls are also shown. Data are represented as mean ± S.E.M; n ≥ 4 axons per independent MN differentiation, N = 3 independent differentiations. Statistical significance was evaluated with the Kruskal–Wallis test with FDR correction. *p < 0.05, **p < 0.01, ***p < 0.001, ‘ns’ denotes non-significant result (p ≥ 0.05)