Page 27 - GTM-3-4

Global Translational Medicine Metabolic dysfunction in vascular senescence

phosphatase and tensin homolog-induced putative kinase ferritin autophagy mediated by nuclear receptor
1 (PINK1) and ubiquitin ligase (Parkin RBR E3 ubiquitin- coactivator 4. Conversely, the inhibition of ferroptosis
protein ligase [Parkin]). Under normal conditions, PINK1 signaling or the activation of peroxisome proliferator-
is guided to the mitochondrial inner membrane by a activated receptor gamma delays vascular senescence,
52
mitochondrial targeting sequence, in which it is cleaved indicating that targeting pro-ferroptosis signals may offer
and hydrolyzed. However, when the mitochondria are a promising strategy for treating senescence or age-related
damaged, their membrane potential decreases, further cardiovascular diseases.
accumulating PINK1 on the outer membrane of the
mitochondria. In addition, Parkin, as an E3 ubiquitin 4. Antisenescence strategies
ligase, is recruited to the damaged mitochondria, in 4.1. Metabolic intervention
which it undergoes phosphorylation and activation by
PINK1. Mitophagy within atherosclerotic plaques plays Metabolism is fundamental to cellular and tissue functions,
46
a crucial role in decomposing and eliminating excessive encompassing energy production, nutrient use, and waste
or impaired mitochondria. Therefore, mitophagy elimination, and is essential for maintaining cellular
47
represents a potential therapeutic target for stabilizing homeostasis. Metabolism dysregulation can disturb the
atherosclerotic plaques, preventing plaque rupture, and cellular energy balance, redox state, and overall functionality,
44
slowing atherosclerosis progression. PINK1 can also subsequently impacting general health and senescence.
48
recruit autophagy receptor proteins (e.g., optineurin Metabolic regulation involves several critical processes,
+
and nuclear dot protein 52) to linear granules through including modulation of the NAD /NADH ratio, blood
+
ubiquitin phosphorylation. These receptors facilitate the glucose control, and caloric restriction. The NAD /NADH
aggregation of microtubule-associated protein 1 light chain ratio plays a crucial role in maintaining the cellular redox
3 (LC3), enabling engulfment of damaged mitochondria balance and energy metabolism, consequently influencing
by autophagosomes. In addition, dysregulation of PINK1- the overall metabolic efficiency. Effective blood glucose
regulation is essential for sustaining metabolic homeostasis
mediated mitophagy may contribute to the progression and preventing metabolic disorders. In addition, caloric
of cardiovascular diseases. Mitochondrial dysfunction is restriction enhances mitochondrial function and reduces
closely linked to the development of conditions such as oxidative stress, which contributes to improved metabolic
atherosclerosis, hypertension, and heart failure. Modulating health and an extended lifespan. These interconnected
53
PINK1 function could enhance mitophagy, potentially factors collectively facilitate metabolic regulation and
alleviating these vascular disorders. 49 Non-ubiquitin- overall well-being.
dependent pathways involve mitophagy receptors rather
than surface proteins. In the PINK1–Parkin-independent 4.1.1. NAD /NADH ratio
+
pathway for mitophagy, PINK1 directly recruits autophagy
receptor proteins (e.g., NIX, BNIP3, and FUNDC1) In redox equilibrium, ROS plays diverse roles in various
through ubiquitin phosphorylation. These receptors can pathophysiological reactions, which are closely associated with
+
facilitate the recruitment of LC3 and Parkin, promoting an increased NAD /NADH ratio and L-2-hydroxylglutaric
acid accumulation. Increased circulating α-hydroxy-butyric
the formation of mitochondrial phagosomes, independent acid levels are associated with an increased NAD /NADH
+
of PINK1’s direct influence. Similarly, mitophagy is ratio and impaired glucose metabolism. Restoring NAD
50
+
54
also affected by external stimuli, such as excess ROS,
nutrient deprivation, and cellular senescence, leading to levels through precursor supplementation reestablishes
+
pathological states such as neurodegenerative diseases, the NAD /NADH ratio, delaying cellular senescence and
metabolic disorders, and senescence (Figure 3). reducing vascular damage. Three main strategies have been
explored for increasing NAD+ levels: (1) supplementing a
3.3. Ferroptosis synthetic precursor of NAD (dietary supplement), such as
β-nicotinamide mononucleotide and nicotinamide ribose,
Ferroptosis is a novel form of regulated cell death that both of which can be obtained through one’s diet and are
differs from other known cell death types, such as apoptosis predominantly used in clinical practice; (2) activating key
55
and necrosis. It is characterized by the accumulation of enzymes involved in NAD biosynthesis, including α-amino-
ferrous iron (Fe ) and oxidative attack on cellular and β-carboxylicmuconate-ε-semialdehyde decarboxylase and
2+
mitochondrial membranes by polyunsaturated fatty the rate-limiting enzyme of the remedial pathway amino
acids. 51 phosphoribosyl transferase; and (3) regulating enzymes
56
Recent studies have demonstrated that pro-ferroptosis related to NAD degradation to maintain cell health
+
signaling contributes to vascular NAD loss, cellular and homeostasis. Increasing NAD levels can enhance
+
57
+
senescence, remodeling, and stiffness by promoting endothelial cell function, improve vascular relaxation, and
Volume 3 Issue 4 (2024) 7 doi: 10.36922/gtm.4619