Changes in the Mitochondria in the Aging Process-Can α-Tocopherol Affect Them?

Abstract

Aerobic organisms use molecular oxygen in several reactions, including those in which the oxidation of substrate molecules is coupled to oxygen reduction to produce large amounts of metabolic energy. The utilization of oxygen is associated with the production of ROS, which can damage biological macromolecules but also act as signaling molecules, regulating numerous cellular processes. Mitochondria are the cellular sites where most of the metabolic energy is produced and perform numerous physiological functions by acting as regulatory hubs of cellular metabolism. They retain the remnants of their bacterial ancestors, including an independent genome that encodes part of their protein equipment; they have an accurate quality control system; and control of cellular functions also depends on communication with the nucleus. During aging, mitochondria can undergo dysfunctions, some of which are mediated by ROS. In this review, after a description of how aging affects the mitochondrial quality and quality control system and the involvement of mitochondria in inflammation, we report information on how vitamin E, the main fat-soluble antioxidant, can protect mitochondria from age-related changes. The information in this regard is scarce and limited to some tissues and some aspects of mitochondrial alterations in aging. Improving knowledge of the effects of vitamin E on aging is essential to defining an optimal strategy for healthy aging.

Keywords: ROS production; inflamm-aging; mitochondrial dynamics; mtDNA; oxidative damage; vitamin E; vitamin E metabolites.

Figure 1

Schematization of mitochondrial dynamic. Mitochondrial fission produces two mitochondria from one mitochondrion, while fusion determines the production of one mitochondrion from two. Proteins involved in the fission processes are dynamin-related protein 1 (DRP1), fission 1 homolog protein (FIS1), mitochondrial fission factor (MFF), mitochondrial dynamics protein of 49 kDa (MiD49), and mitochondrial dynamics protein of 51 kDa/mitochondrial elongation factor 1 (MiD51/MIEF1). The proteins involved in the fusion process are mitofusins 1 and 2 (MFN1 and MFN2), involved in the outer membrane fusion, and OPA1 (long and short forms), involved in the intra-membrane fusion. Disruption in the fusion/fission balance can reduce mitochondrial motility, inducing mitophagy.

Figure 2

Schematic representation of the aging-linked mitochondrial dysfunctions. Aging can induce unbalanced fusion/fission dynamics, accumulation of mitochondrial damage, and impaired mitophagy. The shortened telomerase length activates p53, which reduces PGC-1α expression and, therefore, mitochondrial biogenesis. Furthermore, reduced NAD+ concentration and sirtuin activity led to impaired mitophagy. This may result in increased mitochondrial [Ca²⁺], mPTP formation, and inner mitochondrial membrane potential (MMP) reduction, leading to increased mitochondrial damage. All these factors induce an alteration of mitochondrial biogenesis and functionality, which are at the basis of age-related disorders.

Figure 3

Retrograde signaling pathways. The perturbed mitochondrial network induces an adaptive mechanism. Increased ROS production or mitochondrial dynamic alterations can activate Heme-Regulated Inhibitor (HRI) and General Control Non-derepressible-2 (GCN2), which, in turn, phosphorylate and activate the eukaryotic translation Initiation Factor 2A (eIF-2α). Following its phosphorylation, eIF-2α can induce increased transcription of ATF 2, ATF4, and ATF5, thus activating the nuclear stress-response gene transcription. At the same time, changes in calcium (Ca²⁺), membrane potential (Δψ), ATP/ADP ratio, and NAD⁺/NADH ratio (by a sirtuin-dependent way) can induce the activation of G Protein Pathway Suppressor 2 (GPS2) that can induce the transcription of the nuclear stress-response genes.

Figure 4

Quality control mechanisms to counteract mitochondrial stress. The mitochondrial response to a stress condition changes with the magnitude of perceived stress. It includes (I) the activation of UPR^mt to trigger a transcriptional program to potentially reduce the stress; (II) the removal of damaged proteins by proteases or outer mitochondrial membrane-associated degradation (OMMAD), or of part of damaged portion of mitochondria through mitochondrial-derived vesicles (MDV), to rescue the healthy portion; and (III) mitophagy activation to remove stressed mitochondrion; (IV) induction of cell death to remove the entire damaged cell.

Figure 5

mtDNA and inflammation. Circulating mtDNA binds to the Toll-like receptor 9 (TLR9), which is mainly localized in plasmacytoid dendritic cells, monocytes, B cells, and macrophages and is expressed in the inner face of the endosome membrane. After binding with mtDNA, TLR9 activates an inflammatory response via the nuclear factor kappa-light chain enhancer of activated B cells (NF-kB). In the cytosol of stimulated immune cells, mtDNA can interact with the receptor NLRP3, activating caspase-1, which, in turn, activates the maturation and secretion of pro-inflammatory cytokines IL-1β/IL-18. Alternatively, mtDNA can also bind to the cytosolic sensor of double-stranded DNA (cGAS). Activated cGAS, in turn, activates the adaptor protein STING, leading to the activation of the transcription factor IRF3. IRF3 activates the transcription of genes codifying for IFN-β and IFN-γ.

Figure 6

Vitamin E and its biological function. (A) different vitamin E isoforms; (B) antioxidant activity of vitamin E: conversion of the fat-soluble radicals (LOO^•) into water-soluble radicals (vitamin C radical, Vit.C^•). GSH, reduced glutathione; GSSG, oxidized glutathione.