Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms

Abstract

Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.

Figure 1.

Mitochondrial Dysfunction in Neurodegenerative Pathogenesis. Schematic representation illustrating the central role of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders. Mitochondrial dysfunction, accompanied by increased calcium, lipid peroxidation, elevated reactive oxygen species (ROS), and iron accumulation. These factors collectively serve as a link for key mechanisms contributing to neurodegeneration. The figure highlights the interconnected nature of these pathways and their collective influence on the pathophysiology of neurodegenerative diseases.

Figure 2.

Diagrammatic illustration showing the involvement of mitochondrial processes in ferroptosis. Iron uptake via Mfrn1/2 increases the LIP concentration, promoting mitoROS generation through the Fenton reaction. BID triggers the activation of other proapoptotic proteins, such as BAX and BAK, contributing to ferroptosis. Fatty acids are first converted into fatty acyl-CoA and subsequently enter mitochondria via the carnitine shuttle system. In the matrix, they are again converted into fatty acyl-CoA via ACSF2, providing the specific lipid precursor for β-oxidation. VDAC imports Fe²⁺ into mitochondria. Fe²⁺ contributes to enhanced LIP, which in turn generates mitoROS through the Fenton reaction, thus promoting ferroptosis. CISD1 and ferroportin are involved in the export of mitochondrial iron, the decrease in the mitochondrial iron load and the suppression of ferroptosis. FtMt, by converting Fe²⁺ to Fe³⁺ through its ferroxidase activity and by storing Fe^3+, prevents the Fenton reaction. ACSL4, by converting arachidonic acid to arachidonoyl-CoA, provides a substrate for other enzymes, such as LPCA and LOXs, involved in lipid peroxidation, thereby driving ferroptosis. Glutamine in the cytosol is converted to glutamate by the mitochondrial isoform GLS2. Glutamate is converted to α-KG, thus providing fuel for the TCA cycle and lipid biosynthesis. CS regulates fatty acid synthesis through the release of CoA from acetyl-CoA, a precursor for β-oxidation, thus inducing ferroptosis. Abbreviations used: Mfrn1/2, mitoferrin 1/2; mitoROS, mitochondrial reactive oxygen species; LIP, labile iron pool; BID, BH3 interacting-domain death agonist; BAK, Bcl-2 homologous antagonist killer; BAX, Bcl-2-associated X protein (also known as bcl-2-like protein 4); ACSF2, acyl-CoA synthetase family member 2; VDAC2/3, voltage-dependent anion channels 2/3; ETC, electron transport chain; FtMt, mitochondrial ferritin; CISD1, CDGSH, Iron Sulfur Domain 1; ACSL4, long-chain-fatty-acid—CoA ligase 4; LPCAT, lysophosphatidylcholine acyltransferase; LOXs, lipoxygenase; AA, arachidonic acid; PE, phosphatidylethanolamine; CPT1/2, carnitine palmitoyltransferase 1/2; CoA, coenzyme A; GLS1/2, glutaminase 1/2; CS, citrate synthase; α-KG, alpha-ketoglutarate; TCA cycle: tricarboxylic acid cycle.

Figure 3.

Various signaling pathways involved in mitochondrial quality control, including pathways involved in mitochondrial biogenesis, mitochondrial dynamics through fission and fusion and mitochondrial autophagy (i.e., mitophagy), are involved. Mitochondrial biogenesis is the process of increasing mitochondrial numbers and enhancing mtDNA transcription and translation. Under nutrient- and energy-deprived conditions, the ratio of AMP to ATP significantly increases, which activates cAMP, which in turn activates PKA. PKA is a kinase responsible for phosphorylating CREB. Phosphorylated CREB leads to the translation of PGC-1α, which is responsible for mitochondrial biogenesis. The AMP-to-ATP ratio also leads to the activation of AMPK, which phosphorylates PGC-1α and promotes its nuclear translocation. Similarly, increase in calcium levels also lead to the phosphorylation of PGC-1α and enhance its nuclear translocation via CaMK and p38MAPK. Sirtuins also promote the deacetylation of PGC-1α, thus leading to enhanced mitochondrial biogenesis via association with Nrf1/2 and leading to the synthesis of TFAM, which is responsible for mtDNA transcription and translation. BDNF also plays an important role in phosphorylating CREB and in turn increases the transcription of PGC-1α. A dynamic equilibrium is maintained between biogenesis and mitophagy, as these factors also play important roles in mitophagy. Sirtuins are known to activate various autophagy-related genes. AMPK leads to the increased synthesis of ULK1 and inhibits mTOR, and PGC-1α leads to the nuclear translocation of transcription factor EB (TFEB); these factors together promote mitophagy. In conditions of fission and fusion, Mfn1 and Mfn2 are required for GTP-mediated fusion of the outer mitochondrial membrane, and OPA1 is responsible for fusion of the inner mitochondrial membrane of two healthy mitochondria. Under conditions of neurodegeneration, the membrane potential of mitochondria decreases, which leads to mitochondrial dysfunction, and these mitochondria need to be removed to maintain homeostasis. For elimination, two processes are involved, mitophagy and other fission, to liberate the dysfunctional part of the membrane free from healthy mitochondria. Under conditions of low membrane potential, PINK1 accumulates on the mitochondrial membrane, which, in association with PARKIN, recruits mitophagy-promoting factors such as ATG7, ultimately leading to mitochondrial autophagy. Drp1 in association with PINK1 has been shown to promote mitochondrial fission. FUNDC1, an outer mitochondrial membrane protein, also facilitates Drp1-mediated fission of mitochondria. AMPK was also found to increase Drp1-mediated fission. Parkin interacting substrate (PARIS), which is inhibited by PGC-1α, is ubiquitinated by Parkin; thus, PGC-1α is no longer inhibited, and mitochondrial biogenesis occurs.

Figure 4.

Chemical structure of therapeutic candidates targeting mitochondrial bioenergetics.

Figure 5.

Chemical structure of therapeutic candidates targeting mitochondrial biogenesis.

Figure 6.

Chemical structure of therapeutic candidates targeting mitochondrial dynamics.

Figure 7.

Chemical structure of therapeutic candidates targeting mitophagy.