bims-ciryme 2023-07-09 papers

Issue of 2023‒07‒09
two papers selected by
Gabriela Da Silva Xavier
University of Birmingham

Biochem J. 2023 Jul 12. 480(13): 909-919

Shaping mitochondria through fed-fast and circadian cycles.

Subhash Khatri, Rubina Kazi, Ullas Kolthur-Seetharam.

Energy and metabolic homeostasis at the level of the whole body are dictated by the balance between nutrient intake/utilization, bioenergetic potential, and energy expenditure, which are tightly coupled with fed/fast cycles and circadian oscillation. Emerging literature has highlighted the importance of each of these mechanisms that are essential to maintain physiological homeostasis. Lifestyle changes predominantly associated with altered fed-fast and circadian cycles are well established to affect systemic metabolism and energetics, and hence contribute to pathophysiological states. Therefore, it is not surprising that mitochondria have emerged as being pivotal in maintaining physiological homeostasis through daily oscillations/fluctuations in nutrient inputs and light-dark/sleep-wake cycles. Moreover, given the inherent association between mitochondrial dynamics/morphology and functions, it is important to understand the phenomenological and mechanistic underpinnings of fed-fast and circadian cycles dependent remodeling of mitochondria. In this regard, we have summarized the current status of the field in addition to providing a perspective vis-a-vis the complexity of cell-autonomous and non-cell-autonomous signals that dictate mitochondrial dynamics. We also highlight the lacunae besides speculating on prospective efforts that will possibly redefine our insights into the diurnal orchestration of fission/fusion events, which are ultimately coupled to the mitochondrial output.

Keywords: circadian clock; fed–fast cycles; fission/fusion; metabolic sensing; mitochondrial biogenesis; mitochondrial functions

DOI: https://doi.org/10.1042/BCJ20220378

Nat Cell Biol. 2023 Jul 06.

Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis.

Chantal Alkhoury, Nathaniel F Henneman, Volodymyr Petrenko, Yui Shibayama, Arianna Segaloni, Alexis Gadault, Ivan Nemazanyy, Edouard Le Guillou, Amare Desalegn Wolide, Konstantina Antoniadou, Xin Tong, Teruya Tamaru, Takeaki Ozawa, Muriel Girard, Karim Hnia, Dominik Lutter, Charna Dibner, Ganna Panasyuk.

Metabolic demands fluctuate rhythmically and rely on coordination between the circadian clock and nutrient-sensing signalling pathways, yet mechanisms of their interaction remain not fully understood. Surprisingly, we find that class 3 phosphatidylinositol-3-kinase (PI3K), known best for its essential role as a lipid kinase in endocytosis and lysosomal degradation by autophagy, has an overlooked nuclear function in gene transcription as a coactivator of the heterodimeric transcription factor and circadian driver Bmal1-Clock. Canonical pro-catabolic functions of class 3 PI3K in trafficking rely on the indispensable complex between the lipid kinase Vps34 and regulatory subunit Vps15. We demonstrate that although both subunits of class 3 PI3K interact with RNA polymerase II and co-localize with active transcription sites, exclusive loss of Vps15 in cells blunts the transcriptional activity of Bmal1-Clock. Thus, we establish non-redundancy between nuclear Vps34 and Vps15, reflected by the persistent nuclear pool of Vps15 in Vps34-depleted cells and the ability of Vps15 to coactivate Bmal1-Clock independently of its complex with Vps34. In physiology we find that Vps15 is required for metabolic rhythmicity in liver and, unexpectedly, it promotes pro-anabolic de novo purine nucleotide synthesis. We show that Vps15 activates the transcription of Ppat, a key enzyme for the production of inosine monophosphate, a central metabolic intermediate for purine synthesis. Finally, we demonstrate that in fasting, which represses clock transcriptional activity, Vps15 levels are decreased on the promoters of Bmal1 targets, Nr1d1 and Ppat. Our findings open avenues for establishing the complexity for nuclear class 3 PI3K signalling for temporal regulation of energy homeostasis.

DOI: https://doi.org/10.1038/s41556-023-01171-3