Astaxanthin as a Novel Mitochondrial Regulator: A New Aspect of Carotenoids, beyond Antioxidants

Abstract

Astaxanthin is a member of the carotenoid family that is found abundantly in marine organisms, and has been gaining attention in recent years due to its varied biological/physiological activities. It has been reported that astaxanthin functions both as a pigment, and as an antioxidant with superior free radical quenching capacity. We recently reported that astaxanthin modulated mitochondrial functions by a novel mechanism independent of its antioxidant function. In this paper, we review astaxanthin's well-known antioxidant activity, and expand on astaxanthin's lesser-known molecular targets, and its role in mitochondrial energy metabolism.

Keywords: AMPK; astaxanthin; energy metabolisms; insulin resistance; mitochondria; natural antioxidant; obesity.

Figure 1

Structure of astaxanthin (AX) and related carotenoids.

Figure 2

AX performs its antioxidant activity both inside and on the surface of the plasma membrane. Due to its strongly hydrophobic conjugated polyene structure and terminal polar groups, AX can exist both inside and on the surface of the phospholipid membrane. Therefore, AX is able to exert its effects against ROS both at the surface and inside of phospholipid membranes. On the other hand, β-carotene exerts its antioxidant activity only inside the phospholipid membrane. As for other antioxidants, ascorbic acid cannot exert its effect inside the phospholipid membrane, due to its high hydrophilicity, whereas tocopherols are relatively effective at the surface of the phospholipid membrane. This figure excludes the detailed structure of the cell membrane, including localization of different levels of lipids lipid rafts and proteins to avoid complications.

Figure 3

AX partially induces the antioxidant defense system while inhibiting the ROS-mediated inflammatory signaling pathway. AX inhibits ROS-mediated activation of canonical NFκB signaling and related signals such as JAK/STAT3. Consequently, the induction of pro-inflammatory cytokine gene expression is suppressed, resulting in attenuation of inflammatory signals. On the other hand, AX produces partial activation of Nrf2 via dissociation of Nrf2/Keap-1 by electrophiles, and/or other pathways. Consequently, antioxidant enzymes are induced and act in an anti-inflammatory function in vivo. Thus, AX suppresses the exacerbation cycle of chronic inflammation and shifts the cycle toward improvement. The regulation of these inflammation-related signaling pathways by AX involve a mixture of acute-phase responses to AX that result from ROS scavenging, modulation of phosphorylation and protein modifications related to the regulation of intracellular Redox balance, modulation of adaptor protein association with receptors, and the more chronic induction of gene expression mediated by these results. In this figure, lipid rafts and precise and detailed signal pathways are not shown to avoid complications. In particular, it has been reported that AX affects the points indicated by the orange arrows. This figure was adapted from the reference [70,71].

Figure 4

AX regulates various mitochondria-associated metabolic pathways, mitochondrial biogenesis and its quality control via AMPK activation. (A) AMPK is activated by exercise, energy depletion, or certain active drugs (e.g., AICAR, adiponectin, metformin and imeglimin) by (1) increased Ca2+ influx; (2) direct modification by ROS and activation of MAPKs; and (3) increased AMP/ATP ratio. Activated AMPK induces activation of PGC-1α and related gene expression, leading to enhanced energy metabolisms, adapted metabolic switching, and increased mitochondria biogenesis. Furthermore, AMPK regulates gene expression of Nampt and promotes de novo synthesis of NAD+ in the cell. As a result, it enhances the activity of Sirtuins and further enhances the activity of PGC-1α. Thus, AMPK/Sirtuins/PGC-1α forms a positive feedback loop in their actions. (B) AMPK contributes to mitochondrial quality control; AMPK not only enhances mitochondrial biogenesis, but also regulates mitochondrial fission and fusion via phosphorylation of Mef, and induces mitophagy in autophagosomes via the phosphorylation of Ulk-1 for the impaired mitochondria. AX activates AMPK. In particular, it has been reported that AX affects the points indicated by the orange arrows. In this figure, precise and detailed signal pathways are not shown, to avoid complications. This figure was adapted from the reference [116,133,134].

Figure 4

AX regulates various mitochondria-associated metabolic pathways, mitochondrial biogenesis and its quality control via AMPK activation. (A) AMPK is activated by exercise, energy depletion, or certain active drugs (e.g., AICAR, adiponectin, metformin and imeglimin) by (1) increased Ca2+ influx; (2) direct modification by ROS and activation of MAPKs; and (3) increased AMP/ATP ratio. Activated AMPK induces activation of PGC-1α and related gene expression, leading to enhanced energy metabolisms, adapted metabolic switching, and increased mitochondria biogenesis. Furthermore, AMPK regulates gene expression of Nampt and promotes de novo synthesis of NAD+ in the cell. As a result, it enhances the activity of Sirtuins and further enhances the activity of PGC-1α. Thus, AMPK/Sirtuins/PGC-1α forms a positive feedback loop in their actions. (B) AMPK contributes to mitochondrial quality control; AMPK not only enhances mitochondrial biogenesis, but also regulates mitochondrial fission and fusion via phosphorylation of Mef, and induces mitophagy in autophagosomes via the phosphorylation of Ulk-1 for the impaired mitochondria. AX activates AMPK. In particular, it has been reported that AX affects the points indicated by the orange arrows. In this figure, precise and detailed signal pathways are not shown, to avoid complications. This figure was adapted from the reference [116,133,134].