Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming Reveals Regulators of the Respirasome and Neurogenesis

iScience. 2019 Sep 27;19:1114-1132. doi: 10.1016/j.isci.2019.08.057.

Mohamed Taha Moutaoufik ¹, Ramy Malty ¹, Shahreen Amin ¹, Qingzhou Zhang ¹, Sadhna Phanse ¹, Alla Gagarinova ², Mara Zilocchi ¹, Larissa Hoell ¹, Zoran Minic ¹, Maria Gagarinova ¹, Hiroyuki Aoki ¹, Jocelyn Stockwell ³, Matthew Jessulat ¹, Florian Goebels ⁴, Kirsten Broderick ¹, Nichollas E Scott ⁵, James Vlasblom ¹, Gabriel Musso ⁶, Bhanu Prasad ⁷, Eleonora Lamantea ⁸, Barbara Garavaglia ⁸, Alex Rajput ⁹, Kei Murayama ¹⁰, Yasushi Okazaki ¹¹, Leonard J Foster ⁵, Gary D Bader ⁴, Francisco S Cayabyab ³, Mohan Babu ¹²

Affiliations

1 Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
2 Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
3 Department of Surgery, Neuroscience Research Group, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
4 The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
5 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
6 Department of Medicine, Harvard Medical School and Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
7 Department of Medicine, Regina Qu'Appelle Health Region, Regina, SK S4P 0W5, Canada.
8 Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Instituto Neurologico Carlo Besta, via L. Temolo, 4, 20126 Milan, Italy.
9 Department of Medicine, Division of Neurology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
10 Department of Metabolism, Chiba Children's Hospital, 579-1 Heta-cho, Midori, Chiba 266-0007, Japan.
11 Graduate School of Medicine, Intractable Disease Research Center, Juntendo University, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan.
12 Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada. Electronic address: mohan.babu@uregina.ca.

PMID: 31536960 DOI: 10.1016/j.isci.2019.08.057

Abstract

Mitochondrial protein (MP) assemblies undergo alterations during neurogenesis, a complex process vital in brain homeostasis and disease. Yet which MP assemblies remodel during differentiation remains unclear. Here, using mass spectrometry-based co-fractionation profiles and phosphoproteomics, we generated mitochondrial interaction maps of human pluripotent embryonal carcinoma stem cells and differentiated neuronal-like cells, which presented as two discrete cell populations by single-cell RNA Sequencing. The resulting networks, encompassing 6,442 high-quality associations among 600 MPs, revealed widespread changes in mitochondrial interactions and site-specific phosphorylation during neuronal differentiation. By leveraging the networks, we show the orphan C20orf24 as a respirasome assembly factor whose disruption markedly reduces respiratory chain activity in patients deficient in complex IV. We also find that a heme-containing neurotrophic factor, neuron-derived neurotrophic factor [NENF], couples with Parkinson disease-related proteins to promote neurotrophic activity. Our results provide insights into the dynamic reorganization of mitochondrial networks during neuronal differentiation and highlights mechanisms for MPs in respirasome, neuronal function, and mitochondrial diseases.

Keywords

Biological Sciences; Developmental Biology; Developmental Neuroscience; Proteomics.

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