A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD⁺, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.

Keywords: mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; oxidative stress; plasma membrane redox enzymes.

Figure 1

Regulation of cellular physiology by ROS levels. When ROS levels are very low, the cell cycle can be arrested, and proliferation is slowed. Under normal ROS levels, cells show normal cell physiology (e.g., cellular homeostasis, cell division, synaptic plasticity, etc.) by maintaining appropriate signalling pathways. However, during the aging processes, ROS production is increased due to the attenuated antioxidant defence, resulting in decreased proliferation. When ROS levels are high, they can induce oxidative-stress-induced damage to biomolecules, causing mitochondrial dysfunction and apoptotic cell death.

Figure 2

(A) Mitochondrial biogenesis modulated by SIRT1, NAD⁺, and AMPK. Energetic stress (e.g., high NAD⁺/NADH ratio, increased AMP level) is a good enhancer of mitochondrial biogenesis by activating SIRT1 and PGC1α. CR elevates NAD⁺ level directly or by activating PM redox enzymes or AMPK indirectly. Rafamycin and resveratrol can enhance AMPK activity. (B) The structure of AMPK and the function of AMPK subunits. Each of the subunits plays a different role in AMPK activation. AMPK α subunit activates the AMPK complex, AMPK β subunit stabilises the AMPK complex, and AMPK γ subunit serves as energy-sensor. The activated AMPK complex leads to lipid metabolic change and maintains mitochondrial homeostasis. Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; b5R, cytochrome b5 reductase; CD38, ADP ribosyl cyclase 1; CR, calorie restriction; FOXO, forkhead box transcription factors; MEF2, myocyte-specific enhancer factor 2; mTOR, mammalian target of rapamycin; NQO1, NADH-quinone oxidoreductase 1; NR, nicotinamide riboside; PARP, poly(ADP-ribose) polymerases; PGC1α, PPARγ coactivator 1-α; PPAR, peroxisome proliferator-activated receptor; SIRT, Sirtuin 1.

Figure 2

(A) Mitochondrial biogenesis modulated by SIRT1, NAD⁺, and AMPK. Energetic stress (e.g., high NAD⁺/NADH ratio, increased AMP level) is a good enhancer of mitochondrial biogenesis by activating SIRT1 and PGC1α. CR elevates NAD⁺ level directly or by activating PM redox enzymes or AMPK indirectly. Rafamycin and resveratrol can enhance AMPK activity. (B) The structure of AMPK and the function of AMPK subunits. Each of the subunits plays a different role in AMPK activation. AMPK α subunit activates the AMPK complex, AMPK β subunit stabilises the AMPK complex, and AMPK γ subunit serves as energy-sensor. The activated AMPK complex leads to lipid metabolic change and maintains mitochondrial homeostasis. Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; b5R, cytochrome b5 reductase; CD38, ADP ribosyl cyclase 1; CR, calorie restriction; FOXO, forkhead box transcription factors; MEF2, myocyte-specific enhancer factor 2; mTOR, mammalian target of rapamycin; NQO1, NADH-quinone oxidoreductase 1; NR, nicotinamide riboside; PARP, poly(ADP-ribose) polymerases; PGC1α, PPARγ coactivator 1-α; PPAR, peroxisome proliferator-activated receptor; SIRT, Sirtuin 1.

Figure 3

Regulation of the fusion and fission cycle in the mitochondria, including mitochondrial biogenesis and mitophagy. The mitochondrial fusion/fission cycle is balanced under healthy conditions. However, under diseased conditions, the levels of fusion proteins are decreased, while amounts of fission proteins are increased, resulting in a number of dysfunctional mitochondria. Damaged mitochondria can be combined with lysosomes and degraded. Abbreviations: Drp1, dynamin-related protein 1; Fis1, mitochondrial fission protein 1; Mff, mitochondrial fission factor; Mfn1/2, mitofucin 1/2; Opa1, optic atrophy protein 1.

Figure 4

The PM redox enzymes (NQO1 and b5R) play a crucial role in increasing NAD⁺/NADH ratio and decreasing oxidative/metabolic stress. NAD⁺/NADH ratio is the key factor in inducing cell survival signalling involving SIRT1, PGC1α, and Nrf2. SIRT1 and PGC1α promote mitochondrial biogenesis, and Nrf2 induces ARE expression associated with p300 and FOXO3. Some phytochemicals can break the Nrf2–Keap1 linkage, inducing detoxifying enzymes. Abbreviations: ARE, antioxidant response element; b5R, cytochrome b5 reductase; CBP, transcriptional coactivators of CREB binding protein; CR, calorie restriction; FOXO3, O subclass 3 of the forkhead family of transcription factors. GST, glutathione S-transferase; HO1, heme oxygenase 1; Keap1, Kelch-like ECH-associated protein 1; MAPK, mitogen-activated protein kinase; NF-kb, nuclear factor kappa-light-chain-enhancer of activated B cells; NQO1, NADH-quinone oxidoreductase 1; cNQO1, cytosolic NQO1; mNQO1, membrane-bound NQO1; Nrf2, nuclear factor erythroid-2-related factor 2; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1-α; PKC, protein kinase C; SIRT1, silent mating type information regulation 2 homolog 1.