Analysis of the effect of the mitochondrial prohibitin complex, a context-dependent modulator of longevity, on the C. elegans metabolome

Abstract

The mitochondrial prohibitin complex, composed of two proteins, PHB-1 and PHB-2, is a context-dependent modulator of longevity. Specifically, prohibitin deficiency shortens the lifespan of otherwise wild type worms, while it dramatically extends the lifespan under compromised metabolic conditions. This extremely intriguingly phenotype has been linked to alterations in mitochondrial function and in fat metabolism. However, the true function of the mitochondrial prohibitin complex remains elusive. Here, we used gas chromatography coupled to a flame ionization detector (GC/FID) and 1H NMR spectroscopy to gain molecular insights into the effect of prohibitin depletion on the Caenorhabditis elegans metabolome. We analysed the effect of prohibitin deficiency in two different developmental stages and under two different conditions, which result in opposing longevity phenotypes, namely wild type worms and daf-2(e1370) insulin signalling deficient mutants. Prohibitin depletion was shown to alter the fatty acid (GC/FID) and 1H NMR metabolic profiles of wild type animals both at the fourth larval stage of development (L4) and at the young adult (YA) stage, while being more pronounced at the later stage. Furthermore, wild type and the diapause mutant daf-2(e1370), either expressing or not prohibitin, were clearly distinguishable based on their metabolic profiles, revealing changes in fatty acid composition, as well as in carbohydrate and amino acid metabolism. Moreover, the metabolic data indicate that daf-2(e1370) mutants are more robust than the wild type animals to changes induced by prohibitin depletion. The impact of prohibitin depletion on the C. elegans metabolome will be discussed herein in the scope of its effect on longevity. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. Guest Editor: Aleksandra Trifunovic

Prohibitin in Adipose and Immune Functions

“…Moreover, PHB has been reported to play a role in DNAdamaging agent-induced cellular senescence in MCF-7 and T47D breast carcinoma cell lines, by recruiting specific corepressors to inhibit E2F target genes [82], whereas loss of prohibitins in yeast shortens replicative lifespan [83]. In C. elegans, prohibitin deficiency shortens the lifespan of otherwise wild-type worms, while it dramatically extend the lifespan under compromised metabolic conditions, suggesting a context-dependent role of prohibitins, which has been linked to alterations in mitochondrial function and in fat metabolism [37,84]. More recently, PHB has been identified as the most remarkable protein among the differentially expressed proteins in rat liver as determined by differential proteomic analysis [85].…”

Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

“…This diversity of phenotypes associated to PHB depletion could reflect different consequences of losing one unique biochemical function that remains to be fully clarified. Prohibitin deficiency shortens lifespan in wild-type Caenorhabditis elegans but dramatically extends lifespan in a variety of metabolically compromised animals [16], linking prohibitin functions in mitochondria with cellular metabolism [17]. Lack of PHB complexes induces a strong mitochondrial stress response, the so-called mitochondrial unfolded protein response (UPR mt ) [18][19][20][21], through a non-canonical mechanism [21].…”

Mitochondrial activity and dynamics changes regarding metabolism in ageing and obesity

“…Prohibitin is a complex of two proteins, PHB-1 and PHB-2, that has been associated with longevity in studies carried out in worms (Lourenco et al, 2015). Prohibitins are ubiquitous, evolutionary conserved proteins that form a ring-like complex at the inner membrane of the mitochondria (Artal-Sanz and Tavernarakis, 2009).…”