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Abstract Background NEK10, a serine/threonine/tyrosine kinase belonging to the NEK (NIMA-related kinases) family, has been associated with diverse cellular processes. However, no specific target pathways have been identified. Our previous work knocking down NEK10 in HeLa cells suggested a functional association with mitochondria, as we observed altered mitochondrial morphology, mitochondrial oxygen consumption, mtDNA integrity, and reactive oxygen species levels. Methods To better understand this association, we studied human HAP1 cells fully knockout for NEK10 and confirmed that NEK10 has an important role in mitochondrial homeostasis. We performed the study of mitochondrial respiration, mitochondrial morphology, mitochondrial mass, and mtDNA analysis. Additionally, we showed proteome and phosphoproteome data of crude mitochondrial fraction of Parental and NEK10 KO cells using liquid chromatography-mass spectrometry (LC–MS/MS). Results In the absence of NEK10 several mitochondrial functions were disturbed. Moreover, proteome and phosphoproteome analyses of mitochondrial fractions showed that NEK10 alters the threonine phosphorylation status of several mitochondrial/endoplasmic reticulum components, including HSP60, NDUFB4, and TOM20. These changes impacted the steady-state levels of a larger group of proteins, preferentially involving respiratory complexes and autophagy pathways. Conclusion We concluded that NEK10 plays a key role in mitochondrial function, possibly by modulating the phosphorylation status of mitochondrial proteins.

Mitochondria, the cell’s major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the mitochondria must send signals to the nucleus, which can, in turn, upregulate gene expression to alter metabolism or initiate a stress response. This is known as retrograde signaling. A variety of stimuli and pathways fall under the retrograde signaling umbrella. Mitochondrial dysfunction has already been shown to have severe implications for human health. Disruption of retrograde signaling, whether directly associated with mitochondrial dysfunction or cellular environmental changes, may also contribute to pathological deficits. In this review, we discuss known signaling pathways between the mitochondria and the nucleus, examine the possibility of direct contacts, and identify pathological consequences of an altered relationship.

Abstract Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5–6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.