[Frontiers in Bioscience, Landmark, 22, 854-872, January 1, 2017]

Mitochondria in the pathophysiology of Alzheimer’s and Parkinson’s diseases

Isaac G. Onyango 1 , Shaharyar M. Khan 1 , James P Bennett Jr 2

1Gencia Biotechnology, 706 B Forest St, Charlottesville, VA 22903 USA, 2Neurodegeneration Therapeutics, 3050 A Berkmar Dr, Charlottesville, VA 22901

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Mitochondrial DNA (mtDNA) mutations in AD and PD
4. Mitochondrial biogenesis in AD and PD
5. Mitochondrial oxidative stress
6. Mitochondria and altered calcium homeostasis
7. Mitophagy
8. Mitochondrial stress response signaling
9. Mitochondria and inflammation
10. Conclusion and perspective
11. References

1. ABSTRACT

Mitochondria are responsible for the majority of energy production in energy-intensive tissues like brain, modulate Ca+2 signaling and control initiation of cell death. Because of their extensive use of oxygen and lack of protective histone proteins, mitochondria are vulnerable to oxidative stress (ROS)-induced damage to their genome (mtDNA), respiratory chain proteins and ROS repair enzymes. Animal and cell models of PD use toxins that impair mitochondrial complex I activity. Maintenance of mitochondrial mass, mitochondrial biogenesis (mitobiogenesis), particularly in high-energy brain, occurs through complex signaling pathways involving the upstream “master regulator” PGC-1alpha that is transcriptionally and post-translationally regulated. Alzheimer disease (AD) and Parkinson disease (PD) brains have reduced respiratory capacity and impaired mitobiogenesis, which could result in beta-amyloid plaques and neurofibrillary tangles. Aggregated proteins in genetic and familial AD and PD brains impair mitochondrial function, and mitochondrial dysfunction is involved in activated neuroinflammation. Mitochondrial ROS can activate signaling pathways that mediate cell death in neurodegenerative diseases. The available data support restoration of mitochondrial function to reduce disease progression and restore lost neuronal function in AD and PD.

2. INTRODUCTION

Mitochondrial dysfunction is associated with the aging process and the onset of AD and PD (1-3). Mitochondria constantly generate reactive oxygen species (ROS) as a byproduct of oxygen metabolism (4)and these are important cell signaling molecules (5). With age, mitochondrial DNA (mtDNA) mutations accumulate in post mitotic tissues leading to the malfunctioning of oxidative phosphorylation and an imbalance in the expression of antioxidant enzymes resulting in the net overproduction of reactive oxygen species (ROS)(4,6,7).

Excessive ROS attenuates the bioenergetic function of mitochondria by causing more mutations in nuclear DNA (nDNA) and mtDNA that further impair the tricarboxylic acid cycle (TCA) and the electron transport chain (ETC) complexes. Oxidatively damaged proteins and organelles, such as mitochondria, then accumulate and overwhelm the protein and organelle quality control systems (8-10). This ROS-mediated, progressive mitochondrial damage also affects mitochondrial Ca2+ homeostasis, membrane-permeability and defense systems and elicits a vicious-cycle that amplifies cellular dysfunction that triggers neurodegeneration (4, 6, 7, 11).

The brain is particularly reliant on optimum mitochondrial function because of its high energy demand. It is also especially vulnerable to ROS-induced damage because of its high content of membrane polyunsaturated fatty acids and relatively low anti-oxidant defenses. The brain also possesses of high iron and ascorbate tissue levels which can enhance further ROS generation through the Fenton/Haber Weiss reactions(12).

Alzheimer’s disease (AD) is the most common cause of dementia with an estimated 10% of the world’s population aged more than 60–65 years currently affected and more than 30 million people projected to be affected in the next 20 years (13). Familial AD (FAD) accounts for only 5–10% of all AD cases and usually exhibits an autosomal dominant form of inherited mutation in the amyloid precursor protein gene or the presenilin 1 or 2 genes. Sporadic cases account for 90–95% of all AD cases and usually present in individuals older than 65 years. Evidence from multiple studies show that mitochondrial degeneration and oxidative damage are involved in the pathogenesis of AD (14-16). mtDNA haplogroups influence the risk of AD with the demented parent of an AD patient usually being the mother(17, 18). Transferring mtDNA from AD patients into cell lines devoid of mtDNA (rho0 cells) has been shown to induce respiratory enzyme deficiency similar to that seen in AD tissues. This suggests that the deficit is carried at least in part by mtDNA abnormalities (3). And while AD brains harbor somatic mitochondrial DNA mutations that suppress mitochondrial transcription and replication(19), there is no consensus about causality of mtDNA changes(20).

Base excision repair (BER), the primary mtDNA repair pathway for ROS-mediated small base modifications is impaired in AD and may contribute to the disease pathogenesis, as a significant brain BER deficiency brain correlates with severity in patients with MCI (21). Finally, the pathological features of end-stage AD brains include the presence of phospho-tau neurofibrillary tangles and β-amyloid plaques. Mitochondrial respiratory dysfunction and resultant excessive ROS can result in aberrant accumulation of transition metals, are thought to lead to the accumulation of abnormal β-amyloid or tau- (22-24), can inhibit cytochrome c oxidase (25) and can in turn induce β-amyloid or tau neurotoxicity.

Parkinson’s disease (PD) affects >1% of the population over the age of 6 years and 5% of those over the age of 85 years (26) and is the second most common neurodegenerative disorder (27). The majority (90–95%) of PD cases are non-autosomal, and the remaining 5-10% have been traced to causal dominantly or recessively inherited genes. Both idiopathic and genetic cases of PD exhibit high levels of oxidized lipids, proteins and DNA and reduced glutathione (GSH) levels (28-31). Multiple studies show that the activity of ETC complex I is reduced in PD patients (32-34) and that there are more respiratory chain deficient dopamine (DA) neurons PD patients than in age-matched controls (35). DAergic neurons are particularly prone to oxidative stress since they not only express tyrosine monoamine oxidase and hydroxylase which also generate ROS, but they also contain iron which catalyzes the Fenton reaction, where superoxide radicals and hydrogen peroxide formed can contribute to further oxidative stress (28, 29).

Mutations in genes of mitochondrial proteins DJ-1, Parkin and PINK, which result in mitochondrial dysfunction, are linked to familial forms of PD. Cells which are derived from patients with parkin gene mutation show decreased Complex I activity (36, 37). Mice deficient in parkin gene have reduced striatal respiratory chain activity along with oxidative damage (38, 39). PINK1 mutations induce mitochondrial dysfunction with excess free radical formation (40). Further, of the mutated nuclear genes in PD, α-synuclein, parkin, DJ-1, phosphatase and tensin homologue-induced kinase1, leucine-rich-repeat kinase 2 and HTRA2 directly or indirectly involve mitochondria(16, 36, 41). Rotenone, a specific inhibitor of mitochondrial complex I inhibitor, induces mitochondrial dysfunction and ultrastructural damage with Parkinsonism like symptoms in rats (42). Impaired mitochondrial complex I function is a major source of ROS generation in PD models (16, 29) and in nigrostriatal degeneration in PD patients (43, 44). Also, α-synuclein, although mostly cytosolic, interacts with mitochondrial membranes to inhibit Complex I (45,46) and mice over-expressing mutant α-synuclein have impaired mitochondrial structure and function (47, 48).

3. MITOCHONDRIAL DNA (mtDNA) MUTATIONS IN AD AND PD

MtDNA encodes 13 of the ~92 polypeptides of the OXPHOS system. The remaining structural polypeptides and assembly factors are encoded by nuclear DNA (49, 50). Mitochondria contain many antioxidant and DNA repair enzymes including OGG1 and MUTYH (51-53). However, because of the proximity of the mitochondrial genome to the inner mitochondrial membrane where ROS are routinely generated, and the lack of protective histone molecules, mtDNA has a higher mutation rate than nuclear DNA (54).

mtDNA quality control is important for communication with the nucleus. ROS-mediated gene expression that occurs upon oxidative phosphorylation dysfunction may result in a mitochondrial retrograde signaling pathway that can stimulate an adaptive nuclear response to mtDNA impairment. Mitochondrial genetic alterations can affect the expression of more than 40 nuclear genes (55, 56). On the other hand, mtDNA dysfunction can be induced by many signaling molecules that are regulated by nuclear genes, and by factors related to mitochondrial metabolism (57-60). mtDNA in AD and PD brain are more oxidative damaged with increased mutations/deletions and postgenomic problems with transcriptional regulation than can be attributed to aging(51, 61-64)

4. MITOCHONDRIAL BIOGENESIS IN AD AND PD

Mitochondrial biogenesis is essential for maintaining an adequate functional neuronal mitochondrial mass. It is a highly regulated process that requires coordination and crosstalk between the nuclear and mitochondrial genomes (65) and occurs on a regular basis in healthy cells where mitochondria constantly divide and fuse with each other. Current understanding indicates that mitochondrial biogenesis is regulated by the “master regulator” peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) which in turn activates different transcription factors, including nuclear respiratory factors 1 and 2 proteins (NRF-1 and NRF-2), estrogen-related receptor alpha (ERR-α) and mitochondrial transcription factor A (TFAM)(66-68). NRF-1 and NRF-2 regulate transcription of nuclear and mitochondrial genes involved in OXPHOS, electron transport (complex I–V), mtDNA transcription/replication, heme biosynthesis, protein import/assembly, ion channels, shuttles, and translation(69).

NRF-1 or NRF-2 also contribute to expression of nuclear encoded genes involved in biogenesis including (70) mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B1 or B2 (TFB1M or TFB2M), and mitochondrial RNA polymerase (POLRMT), and mitochondrial transcription termination factor (MTERF), mitochondrial DNA helicase (TWINKLE), single-stranded DNA-binding protein (mtSSB), and POLγB (71, 72) but not POLgA and MTERF3(72). ERRα regulates genes involved in mitochondrial biogenesis, as well as genes involved in gluconeogenesis, oxidative phosphorylation, and fatty acid metabolism (73, 74).

When newly formed daughter mitochondria have been incorporated into the mitochondrial network, mitochondria that have been damaged or that have lost membrane potential are specifically targeted for degradation by mitophagy (75, 76). Mitochondrial biogenesis is impaired in AD as levels of NRF 1, NRF2, and TFAM along with nuclear levels of PGC-1α are reduced in hippocampal tissues from AD brain compared to age matched control brain associated with fewer mitochondria (1, 77, 78). We have shown that in the PD frontal cortex mitochondrial biogenesis is impaired in a manner that correlates with impaired mitochondrial NADH-driven electron flow (34)and PARIS, a Parkin substrate, is known to repress mitochondrial biogenesis by transcriptionally inhibiting PGC-1α expression (79-81).

5. MITOCHONDRIAL OXIDATIVE STRESS

Nox (nitrogen oxides)-dependent oxidative stress induce neurodegenerative diseases through the oxidation of DNA, proteins, lipids, amino acids and metals, as well as the activation of redox-sensitive signaling pathways (82). AD brains have activated Nox, that are thought to contribute to AD neuropathology (83,84). Abnormal Nox activation is also thought to play an important role in PD pathology (85). ROS can induce permeability transition pore (PTP) opening resulting in mitochondrial swelling, rupture, release of cytochromec, and neuronal death in the progression of these neurodegenerative diseases.

p66Shc, a mitochondria-targeted redox enzyme, has recently been identified to become activated by oxidative stress by phosphorylation at residue Ser36 which then translocates to the mitochondrial inner membrane space. It accumulates in aged mitochondria. Genetic inactivation of p66Shc preserves neuronal viability and mitochondrial integrity in response to oxidative challenges (86). p66ShcA-deficient mice are more resistant to oxidative stress and lived longer than the wild-type animals (87). p66ShcAis implicated in the degenerative pathology of PD and its phosphorylation at Ser36 is significantly increased in PINK1 deficient cell lines under normal tissue culture conditions, and enhanced in the presence of compounds which elicit oxidative stress (88).

ROS can induce the accumulation of misfolded proteins that, in turn, further enhance oxidative stress(89,90). ROS damage proteins by directly oxidizing them and also by impairing the activity of immunoglobulin heavy chain binding protein (Bip) and protein disulfide isomerase (PDI) in the endoplasmic reticulum thereby affecting the protein folding process during aging (91). With age, sirtuins (SIRT) levels as well as antioxidant gene expression and activity decline (92) resulting in increased ROS levels. SIRT3 deacetylates and activates MnSOD in the mouse liver (93) and also increases the activity of isocitrate dehydrogenase 2 during aging, thereby stimulating the tricarboxylic acid (TCA) cycle in the mouse brain (94). This event increases the amount of mitochondrial NADPH and protects against oxidative-stress-induced damage by increasing the ratio of reduced-to-oxidized glutathione. SIRT1 also promotes antioxidant defense through the activation of Forkhead box protein O1 (FOXO1) signaling in multiple mammalian cell lines (95). SIRT3 expression level was found to be reduced in aged skeletal muscle (96). AMPK can stimulate the antioxidant response through FOXO1 activation (97) and ROS-dependent AMP-activated protein kinase (AMPK) inhibition leads to a reduction of antioxidant defenses during aging.

6. MITOCHONDRIA AND ALTERED CALCIUM HOMEOSTASIS

Perturbations in Ca2+-homeostasis are evident in AD (98-102) and PD (103-105) and deregulation of Ca2+-homeostasis, arising from mitochondrial dysfunction, is linked to neurotoxicity (100, 106-108). Mitochondria buffer cytosolic Ca2+-by internalizing it mainly through uniporter and releasing it by Na+-/Ca2+-or H+-/Ca2+-exchangers (106). Cytosolic Ca2+-levels play an important role in normal neurotransmission, long and short term plasticity and regulation of gene transcription in the CNS (109-111) and the levels are carefully buffered by mitochondria. The mitochondrial Ca2+ buffering capacity of the CNS declines with age likely due to cumulative oxidative damage to mitochondria(112). Exposure of phosphatidylserine (PtdS) on the cell surface, a sign of cellular energy deficiency, enhances the ability of β-amyloid to associate with the membrane (113). Neurons with reduced cytosolic ATP levels and elevated surface PtdS levels are particularly vulnerable to β-amyloid toxicity (114, 115) and in AD, β-amyloid oligomers form Ca2+ -permeable channels in membranes (116).

In sporadic PD and in PD animal models calpain is activated (117), and it has been observed that the DAergic neurons expressing high levels of the CaBP calbindin are relatively spared (105). a-synuclein protofibrils generate ion pores in synthetic lipid membranes (118) and induce Ca2+ influx in neurons (119, 120). Substantia nigra pars compacta dopaminergic neurons, unlike other neurons, use CaV1.3. L-typeCa2+ channels (121) and this continuous Ca2+ influx creates an excessive metabolic load that makes them particularly vulnerable to secondary insults on mitochondrial function (122).

7. MITOPHAGY

Mitophagy is the process by which damaged ordysfunctional mitochondria are selectively engulfed by autophagosomes and delivered to lysosomes to be degraded and recycled by the cell (123). Alterations in the mitophagic pathway have been implicated in AD and PD (124-126) and mitochondria have been shown to be key targets of increased autophagic degradation in AD and PD (127). An excess of reactive oxygen species (ROS) may function as an autophagy trigger(128) and dysfunctional mitochondria that overproduce ROS, are indeed selectively targeted for mitophagy (129). Central to mitochondrial and cellular homeostasis, mitophagy is modulated by the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway (130) which primarily targets mitochondria devoid of membrane potential (Δψm). PINK1 accumulate on the outer membrane of dysfunctional mitochondria and recruit the E3 ubiquitin ligase Parkin (131-133) that ubiquitinate several OMM proteins that are consequently targeted by P62/SQSTM1(134).

p62 recognizes ubiquitinated substrates and directly interacts with autophagosome-associated LC3 to recruit autophagosomal membranes to the mitochondria(135). Damaged mitochondria can also, independently of Parkin, increase FUNDC1 and Nix expression to recruit autophagosomes to mitochondria via direct interaction with LC3(136, 137). Ubiquitin ligases, like Smurf1, target depolarized mitochondria for mitophagy (138-140). The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) partly regulates p62 expression due to the presence of an antioxidant response element (ARE) in its promoter region (141, 142). Electrophilic natural products such as isothiocyanate compound, sulforaphane which upregulate Nrf2 by interfering with its regulator protein, the redox sensitive ubiquitination facilitator Keap1 (Kelch-like ECH-associated protein 1) can potentially induce p62 expression (143-145). p62-mediated mitophagy inducer (PMI) (HB229), was recently developed to upregulate P62 via stabilization of Nrf2 and promote mitophagy. This compound bypasses the upstream steps of the mitophagic cascade and acts independently of the Δψm collapse, and does not mediate any apparent toxic effects on mouse embryonic fibroblast (MEF) cells at the concentrations used in the assays (146). Parkin also modulates transport of mitochondria along microtubules to a perinuclear region where autophagosomes are concentrated(147,148). This is likely due to Parkin-mediated turnover of Miro, a protein required to tether kinesin motor protein complexes to the OMM (149). HDAC6, a ubiquitin-binding protein deacetylase is also recruited to mitochondria by Parkin (150) along microtubules (151,152). Mitophagy is crucial for cellular homeostasis and its impairment is linked to several neurodegenerative diseases (153, 154). However, selective pharmacologic modulators of mitophagy that would facilitate dissection of the molecular steps involved in the removal of mitochondria from the network via this pathway are not presently available.

8. MITOCHONDRIAL STRESS RESPONSE SIGNALING

Mitochondria produce most of the cellular ROS and the stress signaling that induces cellular senescence and apoptosis (155-159). Amajor consequence of increased ROS and altered cellular redox state is the oxidation of thiol groups in cysteine residues in relevant proteins (155). FoxO are activated in response to elevated ROS levels and induce anti-oxidant responses (increased expression of catalase and SOD2), cell cycle arrest and/or cell death (160,161). Mitochondrial Akt, GSK-3β, PKA, Abl, PKC, Src and Atm modulate the cellular stress response (162-169). Akt phosphorylates and inactivates GSK-3β, which can localize to the mitochondria. Mitochondrial GSK-3β phosphorylates MCL-1 and VDAC (166, 170) leading to MCL-1 degradation and induction of apoptosis(170). The phosphorylation of VDAC by GSK-3β results in increased mitochondrial membrane permeability which also leads to apoptosis (166, 171). GSK-3β can also phosphorylate and promote the proteasomal degradation of c-Myc, cyclin D1, and β-catenin (172, 173). Hypoxia and other physiological stresses can induce the translocation of PKA to mitochondria (174, 175) causing to bind through Rab32 and other A-kinase AKAPs (163) resulting in the phosphorylation of VDAC (164), Drp1(174), and other mitochondrial proteins.

Hypoxia, by inducing SIAH2, a mitochondrial ubiquitin ligase, destabilizes AKAP121 and limits oxidative capacity under conditions of low oxygen. Interestingly, AKAP121 also appears to promote mitochondrial localization of Src-tyrosine kinase (176) where Src appears to regulate CO activity and respiratory activity (176, 177), and other mitochondrial substrates for Src family kinases are likely (178). Increased ROS induces protein kinase C-delta (PKCδ) association with the mitochondria and this in turn recruits other signaling molecules, including the Abl tyrosine kinase that is associated with loss of membrane potential and non-apoptotic cell death (167). Impaired oxidative metabolism and decreased ATP levels in neurons activate AMPK(179). AMPK can also be activated by drugs such as metformin that inhibits complex I or resveratrol that inhibits the F0F1 ATPase(162). AMPK modulates mitochondrial metabolism and targets Acetyl CoA carboxylase-2 (ACC2) to the OMM where it regulates lipid metabolism by controlling production of malonyl CoA(162). AMPK therefore plays a key role in mitochondrial homeostasis by ensuring that only functionally viable mitochondria are retained. Upon its activation it induces not only mitochondrial biogenesis through activation of PGC-1α (180, 181) but also initiates mitophagy through ULK1 activation and mTOR inhibition(174, 182).

ATM kinase inhibition causes CNS neurodegeneration in animal models (183). ATM kinase, is partly located at the mitochondria and is activated by mitochondrial uncoupling (184). While the mitochondrial substrates of ATM are not known, loss of ATM in genetically engineered mouse models leads to mitochondrial dysfunction. ATM signaling is reduced in the neurons in vulnerable regions of the AD brain (185). ATM is also involved in the pathogenesis of PD because ATM gene knockout (ATM KO) mice exhibit severe loss of tyrosine hydroxylase-positive DA nigro-striatal neurons, and midbrain DA neurons progressively degenerate with age (186) and cancers, PARK2 and ATM mutations sometimes occur synchronically at the same amino-acid residue, causing neuronal degeneration (187). This overlap suggests that cancers and PD may adopt similar mechanisms. ATM deficient neurons re-enter the cell cycle and die (188, 189), suggesting that ATM may protect neuron by stopping cells re-entering the cell cycle and lessening DNA damage. ATM impairment in glial cells may also trigger innate immune responses leading to cause neurodegeneration (183). The histology of microglial cell in ATM KO mice was abnormal, and astrocytes from ATM KO mice showed significant expressions of oxidative and endoplasmic reticulum stress and a senescence-like reaction (190, 191). ATM deficiency may disturb DNA repair, trigger apoptosis, and accelerate aging and neuroinflammation.

9. MITOCHONDRIA AND INFLAMMATION

The induction of ROS is thought to lead to the generation of a possible ligand of NLRP3 or to directly affect NLRP3 or associated proteins and most NLRP3 activators also cause ROS generation in immune cells such as macrophages and monocytes (192). NLRP3 stimuli induced a translocation of NLRP3 from the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), where it forms a functional inflammasome with caspase-1 and ASC (193). Mitochondria serve as the scaffold for NLRP3 inflammasome formation, where mitochondrial ROS and oxidative metabolism regulate caspase-1 activation, the critical step in maturation of Il-1beta and Il-18. Mitochondrial oxidative metabolism regulates macrophage polarization, T-cell activation, differentiation and memory cell formation (for review see Weinberg et al., 2015(194).

Thus, mitochondria not only sustain immune cell phenotypes but also are necessary for establishing immune cell phenotype and function. In a pro-inflammatory state this is accomplished by mitochondria shifting from producing ATP via oxidative metabolism to producing building blocks for macromolecule synthesis via anapleurosis and glutaminolysis. The shift from catabolism to anabolism is critical to affect cell expansion, production of inflammatory mediators and immune cell fate commitments. This may explain why the increase in serum pro-inflammatory cytokines occurs with age, giving rise to a chronic state of inflammation, termed inflamm-aging (195, 196). In AD, immune dysfunction has been identified in T-and B-cells, macrophages and microglia (197). AD is associated with increased T cell infiltration, changes in immune populations associated with disease progression, reduction in T-and B-cell numbers and reductions in CD4+CD25+ Tregs (198). CD8+CD28-suppressor cells are also decreased in PBMCs from AD patients. These data suggest that the immunosuppressive capabilities in AD patients are diminished and could represent a deficit in the ability to control Teff responses. As such, increased activities of Th17, levels of IL-21, IL-6, and IL-23, and the Th17-associated transcription factor RORγ, were increased among lymphocytes in AD patients (199). This suggests AD specific overactivity of Th17 T-cell function and underactivity of Teff function. Given that Th17 T-cells primarily mobilize glycolysis and suppress OxPhos whereas Tregs and memory Tcellsoxidize fatty acids via mitochondrial oxidation, supports the concept that mitochondrial dysfunction fuels AD immune dysfunction (200).The neurodegenerative process in PD is accompanied by a neuroinflammatory response, that’s mediated by the activation of microglia cells(201, 202) which release the pro-inflammatory TNF-α and IL-1β cytokines(203, 204) resulting in the accumulation of ROS that adversely affects adjacent neurons (39, 205). Many PD-linked genetic mutations are involved in the regulation of the immune system (206), and it is likely that genetic vulnerability predisposes to the development of midbrain DA neurodegeneration via inflammatory mechanisms. There is also a peripheral immune dysfunction observed in PD (207, 208). The abnormalities in peripheral T cells, including decrease in the number of CD4(+) T cell subsets and Treg dysfunction are observed in PD patients (209-211).

10. CONCLUSION AND PERSPECTIVE

Several lines indicate that mitochondria play a critical role in the pathogenesis of AD and PD. The present therapeutics for these diseases are at best symptomatic and not neuroprotective or neurorestorative.

Therapeutic strategies such as mitochondria-targeted antioxidants have shown promise in various animal models. In addition, pharmacological or nutritional approaches (e.g.,caloric restriction and caloric restriction mimetics such as resveratrol) targeting on evolutionarily conserved, Nrf2/ARE-driven, or sirtuin-dependent pro-survival pathways that upregulate intrinsic antioxidant systems in mitochondria, are being explored as potential therapeutic targets. Interventions modulating processes involved in the regulation of mitochondrial turnover are also of particular interest.

Significant research effort is still required to elucidate the complexity of the network of multileveled, cross-talk that regulate mitochondrial homeostasis. This knowledge will likely provide novel and highly effective treatment to slow, stop or reverse the neurodegenerative process in AD and PD. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events involving energy provision, redox and Ca2+homeostasis, cellular and intra-inter-organellar quality control, regulation of cell death/survival pathways resulting in neurodegeneration in AD and PD, significant research effort is still required to elucidate the complexity of the network of multileveled, cross-talk that regulate mitochondrial homeostasis and identify potential multifunctional therapeutic targets that will improve mitochondrial function, attenuate oxidative stress, and optimize mitochondrial quality control in neurons and slow or halt progressive course of these neurological disorders. This knowledge will likely provide novel and highly effective treatment to slow, stop or reverse the neurodegenerative process in AD and PD.

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Key Words: Alzheimer’s Disease, Parkinson’s Disease, Mitochondria, Mitophagy, Oxidative Stress, Mitochondrial Biogenesis, Mitochondrial Dynamics, Neuroinflammation, Immunoaging, Review

Send correspondence to: Isaac G. Onyango, GenciaBiotechnology, 706 B Forest St, Charlottesville, VA 22903 USA, Tel: 434-295-4800, Fax: 434-295-4951, E-mail: ionyango@genciabiotech.com