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

Abstract

SummaryMitochondrial 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.

Mitochondria under the spotlight: On the implications of mitochondrial dysfunction and its connectivity to neuropsychiatric disorders

“…As we have recently described [10] , several network-based approaches can be used to map mt interactome perturbations in NPDs. For example, mt protein complexes can be studied under native conditions by biochemical fractionation and mass spectrometry (MS), which can capture strong, as well as weak, transient or low abundance interactors using cross-linkers in neuronal cells [94] and mammalian brain [95] . Notably, this method can map loss- or gain-of-function PPIs between NPD patients vs. healthy controls.…”

The Concept of an Epilepsy Brain Bank

“…In 1968, Dr. Ali Rajput created the first brain bank in Canada dedicated only to patients with Parkinson's disease (PD) and other movement disorders. Development of the Bank led to numerous international and local contributions and critical breakthroughs in the modern treatment of PD, only possible because every case has the full documentation of 1 (1) detailed longitudinal clinical history, frozen tissue, and complete neuropathologic examination (2)(3)(4)(5)(6). The bank has more than 400 brains from patients with PD and other movement disorders and it shares samples with national and international qualified scientists for free (1).…”

Características comunes de las chaperonas pequeñas y diméricas

“…La Hsp31 en las levaduras se transloca del citoplasma a las mitocondrias durante condiciones de estrés, principalmente estrés oxidante, y contribuye a preservar la integridad mitocondrial manteniendo el NADPH y por ende el glutatión (Aslam & Hazbun, 2016;Bankapalli et al, 2015). En humanos, DJ-1 no sólo se localiza en el citoplasma, la mitocondria y los cuerpos de estrés, sino también en el núcleo, en el aparato de Golgi, en el retículo endoplásmico y en las balsas lipídicas de la membrana celular (Kim et al, 2013;Kim et al, 2012;Moutaoufik et al, 2019;Usami et al, 2011).…”