OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway

Abstract

How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, produced by these pathways enter mitochondria for ATP production and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH shuttling- and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by a high AMP/ATP ratio. In OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Dgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2 and NRG1) controlled by SNF1 signaling. Our results are interpreted in terms of a mechanism by which peroxisomal and mitochondrial proteins and/or metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol and the nucleus. We discuss the physiological relevance of this work in the context of human OXPHOS deficiencies.

Convergent and divergent mechanisms of peroxisomal and mitochondrial division

“…This is illustrated by the fact that mitochondria with higher respiration rates are more elongated, whereas non-respiring mitochondria become fragmented through fission ( Plecitá-Hlavatá et al, 2008 ). Mitochondria defective in oxidative phosphorylation are also unable to proliferate POs in P. pastoris ( Farre et al, 2022 ).…”

Peroxisomal compartmentalization of amino acid biosynthesis reactions imposes an upper limit on compartment size

“…Delivery of proteins across the peroxisomal membrane is mediated by two cargo receptors binding to the specialized cis-motifs on cargo proteins – the PTS1-type receptor Pex5 and the PTS2-type receptor Pex7 (Gatto et al, 2000; Pan et al, 2013). Changes in peroxisome size and number have been associated with environmental stimuli in many organisms (Deb et al, 2022; Farre et al, 2022; Reddy et al, 1980; Reddy and Krishnakantha, 1975; Veenhuis et al, 1979; Veenhuis et al, 1987) and human disease (Jean Beltran et al, 2018; Legakis et al, 2002; Waterham et al, 2016).…”