Integration of peroxisomes into an endomembrane system that governs cellular aging

Abstract

The peroxisome is an organelle that has long been known for its essential roles in oxidation of fatty acids, maintenance of reactive oxygen species (ROS) homeostasis and anaplerotic replenishment of tricarboxylic acid (TCA) cycle intermediates destined for mitochondria. Growing evidence supports the view that these peroxisome-confined metabolic processes play an essential role in defining the replicative and chronological age of a eukaryotic cell. Much progress has recently been made in defining molecular mechanisms that link cellular aging to fatty acid oxidation, ROS turnover, and anaplerotic metabolism in peroxisomes. Emergent studies have revealed that these organelles not only house longevity-defining metabolic reactions but can also regulate cellular aging via their dynamic communication with other cellular compartments. Peroxisomes communicate with other organelles by establishing extensive physical contact with lipid bodies, maintaining an endoplasmic reticulum (ER) to peroxisome connectivity system, exchanging certain metabolites, and being involved in the bidirectional flow of some of their protein and lipid constituents. The scope of this review is to summarize the evidence that peroxisomes are dynamically integrated into an endomembrane system that governs cellular aging. We discuss recent progress in understanding how communications between peroxisomes and other cellular compartments within this system influence the development of a pro- or anti-aging cellular pattern. We also propose a model for the integration of peroxisomes into the endomembrane system governing cellular aging and critically evaluate several molecular mechanisms underlying such integration.

Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome

“…These cellular processes include the following: (1) glycogen degradation; (2) the glycolytic pathway; (3) the pentose phosphate pathway; (4) pyruvate conversion to acetyl-CoA; (5) the maintenance of redox balance between NAD and NADH with the help of carnitine and glycerol-3-phosphate shuttles; (6) ROS detoxification; (7) stress response; (8) glutathione synthesis; (9) gluconeogenesis; (10) ethanol formation; (11) the synthesis and hydrolytic degradation of triacylglycerols (TAG) and ergosteryl esters (EE), the 2 major neutral lipids; (12) the synthesis of various amino acids; (13) nucleotide synthesis; (14) the assembly of the 40S and 60S ribosomal subunits from numerous protein components whose levels were altered by LCA; and (15) proteasomal and vacuolar protein degradation. 4,5,39,41,38,71,72 We then subjected cellular proteins whose levels were changed in yeast grown in a medium supplemented with LCA to bioinformatic analysis with the help of the SPELL online search engine, 51 as described above for mitochondrial proteins. Just as our bioinformatic analysis of mitochondrial proteins revealed (see above), we found that each of the cellular proteins whose level was altered in yeast cultured with LCA belongs to the following 2 multi-clustered regulons: (1) the PMD regulon, which consisted of the rho 0 (Rtg2p governed) cluster, S1 cluster, general TCA cycle dysfunction cluster, kgd1D, kgd2D or lpd1D cluster, yme1Dmdl1D Figure 2.…”

Pex35 is a regulator of peroxisome abundance

“…It is not surprising therefore that malfunction of peroxisomes leads to peroxisome-specific diseases (Braverman et al, 2013;Weller et al, 2003) and contributes to the pathology of Alzheimer's and Parkinson's diseases, aging, cancer, type 2 diabetes and heart failure (Beach et al, 2012;Colasante et al, 2015;Fransen et al, 2013;Islinger et al, 2012;Trompier et al, 2014). A useful distinction divides peroxisomal diseases into two groups: those in which single enzymatic functions are defective, and those where peroxisome biogenesis is defective per se.…”

Metabolomic and Lipidomic Analyses of Chronologically Aging Yeast

“…Due to the relatively short and easily monitored replicative and chronological life spans of this genetically and biochemically manipulable unicellular eukaryote with annotated genome, it has been successfully used to (1) identify numerous novel longevity genes, many of which have been later implicated in regulating longevity of multicellular eukaryotic organisms; (2) establish the chemical nature of molecular damage that causes cellular and organismal aging and accelerates the onset of age-related diseases; and (3) identify a number of longevity-extending small molecules, many of which have been later shown to slow down aging, improve health, attenuate age-related pathologies and delay the onset of age-related diseases in multicellular eukaryotes [3,5,8,9,[18][19][20][21][22][23][24][25][26][27][28].…”