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Mitochondrial Dysfunction and Alzheimer’s Disease

//Mitochondrial Dysfunction and Alzheimer’s Disease

Mitochondrial Dysfunction and Alzheimer’s Disease

2022-05-22T01:41:10-07:00 May 22nd, 2022|Literature Review|

By Nathifa Nasim, Neurobiology, Physiology, and Behavior ‘22

Author’s note: Based on my interest in exploring Alzheimer’s pathology, I have been interested in the molecular mechanisms that drive neurodegeneration. After working on a project on mitochondrial blockers and Alzheimer’s disease at the Jin lab at the MIND Institute, I found numerous intersections between neurodegeneration and mitochondrial dysfunction, which I seek to explore in this review.

 

Introduction

Mitochondria are critical for energy production across the body, and are especially crucial in the brain. Not only does the brain require significantly more energy in relation to its mass compared to other organs, but it also has limited glycolytic capacity (the maximum rate of glycolytic ATP production) relying mostly on oxidative phosphorylation for meeting its high energy demands [1]. Due to this, complications with the brain’s mitochondria that affect its capacity for oxidative phosphorylation can have severe consequences on overall cognitive function. Mitochondrial dysfunction has been implicated in the pathology of various neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease, Leber’s hereditary optic neuropathy, and, the focus of this review, Alzheimer’s disease (AD) [2]. Although the exact mechanisms behind the progression of AD is still unclear, recent research points towards various ways in which abnormalities in oxidative phosphorylation, or more specifically, the mitochondrial electron transport chain (ETC) – a series of protein complexes which are the sites of oxidative phosphorylation – result in various types of cellular damage which align with various hallmarks of AD pathology such as atrophy, AB aggregation, and cognitive decline. 

Electron Transport Chain Deficiency

Impaired energy metabolism is one of the earliest and most well-documented signs of AD [4, 5]. As the mitochondria is primarily responsible for cellular energy production, this appears to directly implicate some aspect of mitochondrial dysfunction in the disease pathology. Supporting this, mitochondrial abnormalities in AD brains have been observed even before the emergence of neurofibrillary tangles, one of the key pathological indications of AD; this suggests that mitochondrial dysfunction is one of the earliest steps in AD pathology [4].

Research has verified that the deterioration of energy production in the AD brain was not caused by a lack of mitochondria, but rather deficiency in the electron transport chain [2]. The ETC is one of the means by which the cell produces ATP: four complexes utilize energy from electrons to create a proton gradient, and the influx of protons is coupled to ADP phosphorylation. Parker, et al studying various aspects of the mitochondrial electron transport chain, found an overall decrease in activity of all enzyme complexes involved in the ETC, especially in the cytochrome c oxidase, one of the last steps of the ETC. This was supported by previous research identifying significant decreases in cytochrome c oxidase activity [2, 7]. The brain’s continuous need for energy means that a short period without glucose or oxygen leads to cell death. Therefore, damage to the complexes of the ETC results in neuronal death and atrophy due to the lack of energy production, which is characteristic of AD [1]. 

ETC Damage linked to Free Radical Production

As the ETC is linked to AD characteristics, the ETC is also a source of toxic free radicals, including hydrogen peroxide, hydroxyl, and superoxide, which can lead to cellular damage which also aligns with other AD hallmarks [1]. There are other processes in the cell that also contribute to redox reactions, such as the plasma membrane oxidoreductase system, but we focus on the mitochondria, and specifically the ETC’s production of these free radicals. Oxygen is reduced as the final electron acceptor to drive oxidative phosphorylation. As cytochrome c oxidase is most directly involved with oxygen in this last step, damage to cytochrome c oxidase, as well as the rest of the complexes, can directly increase reactive oxygen species (ROS) [2, 6]. ROS are free radicals which are byproducts of energy metabolism. They are maintained by a balance between production via the ETC and clearance via antioxidants and other enzymes [6, 12]. When the ETC is damaged, the electrons which pass through the chain build up earlier in the chain, such as in complex I, where the electron can be donated to molecular oxygen and create a free radical [1]. Under typical conditions, there are cellular processes in place to neutralize the free radicals, but if there is overproduction exceeding the cell’s capability to transform them, the excess of free radicals creates oxidative stress [1]. 

The effects of free radicals are heightened in the brain, resulting in oxidative damage that aligns with AD hallmarks. As previously mentioned, the brain has a high demand for oxygen in addition to a high iron content, both of which enable ROS production. The brain is also especially vulnerable to ROS damage due to comparatively lower antioxidant defenses. Furthermore, the brain is the final destination of many polyunsaturated fatty acids throughout the body – such as omega-3 fatty acids – and the increased polyunsaturated fatty acids in the membranes are more sensitive to free radical damage due to lipid peroxidation, or when lipids with carbon-carbon double bonds are attacked by free radicals [1]. Synaptic mitochondria are typically more affected by oxidative stress, which leads to synaptic damage and loss, thereby affecting neurotransmission [8]. The organismal effect of this may be cognitive decline, characteristic of AD. Oxidative stress can also lead to atrophy. When EC dysfunction and oxidative stress passes a certain threshold, molecules stored within the mitochondria are released due to increased permeability of its membranes; this is part of the pathway that leads to cell death activation [6]. As mentioned, widespread atrophy or neuronal death is characteristic of AD pathology, which also results in cognitive decline. In addition to these two ways in which ROS is linked to AD, ROS damage is also involved in a positive feedback chain, exacerbating its effects. Additionally, overproduction of ROS induces conformational changes in proteins that affect ETC function causing them to “shut down” the mitochondria; the resulting dysfunction increases ROS levels, creating a cyclical spiral towards widespread atrophy [6]. 

mTDNA, Aging, and Alzheimer’s

Another critical effect of ROS is damage to mitochondrial DNA (mtDNA). Free radicals such as ROS can cause DNA double strand breaks, protein crosslinking, and mutations via base modifications [5]. The mitochondria is especially susceptible to DNA damage as mtDNA lacks histones. In nuclear DNA, histones are proteins that tightly wind DNA, which protects against UV damage, for instance, by reducing the exposed surface area; studies have indicated that this organization protects against free radical damage as well. mtDNA’s lack of histones due to its smaller size results in greater possibility of free radical damage [1, 5]. Moreover, the proximity of the mtDNA to the site of ROS production (in the mitochondria) also increases the likelihood of damage [5]. 

The mtDNA mutations are especially apparent in AD, primarily due to the mutations’ connection to the ETC. Studies have indicated increased oxidative damage of mtDNA in AD patients, notably a three-fold increase compared to healthy brains [5]. A study of AD patients also identified the specific sequences of mtDNA which most commonly suffer damage, and these were linked to the activities of the complexes of the ETC [9], and specifically, to decrease cytochrome oxidase activity [5]. As previously discussed, these damages to the ETC ultimately result in neural loss and damage which may explain the cognitive decline in AD patients [1,6]

Research suggests that ETC activity lowers with age, and one of the hypotheses behind this correlation is the accumulation of mutations with age [6]. As age is one of the risk factors for AD, the question arises whether the accumulation of mtDNA mutations and damage is simply a result of aging as AD is diagnosed later in life. A study exploring this identified higher mutation rates in mtDNA in some, but not a majority, of AD brains. They suggest that although mtDNA mutations increase with age, the mutation rate of some individuals is higher, leading to a higher probability of AD-specific mutations which increase the likelihood of dementia [9]. 

Mitochondrial Damage and AB

Given the involvement of mitochondrial dysfunction in AD pathology, research is being conducted to elucidate the connection between it and one of the primary characteristics of AD: amyloid plaques. Amyloid plaques are conglomerations of AB protein, which results from irregular splicing of the amyloid precursor protein (APP.) The nature of APP’s interaction with mitochondria can be explained either by overproduction of APP leading to mitochondrial dysfunction, or mitochondrial damage somehow triggering amyloid plaques. 

AB has been shown to interfere with mitochondrial function through inhibiting cytochrome oxidase activity, and therefore increasing free radical activity and damage [7]. On the other hand, it has also been observed that inhibition of cytochrome oxidase promotes APP cleavage to AB, resulting in another positive feedback loop where AB inhibits the ETC and causes resulting damage, whereas the inhibition itself also promotes AB [6]. Furthermore, a study found that deficiencies in the ETC, and consequent ATP depletion, increased the possibility of APP cleavage to the AB isoform prone to aggregation, possibly due to more exposure to proteases [3, 10]. This would result in the accumulation of amyloid plaques characteristic of AD. The upregulation of mitochondrial genes in AD patients also supports a connection between the organelle and AD pathology [7], as it may be a compensatory response to the detrimental effects of APP on mitochondrial function. 

One hypothesis to explain the means by which APP interferes with mitochondria is that mutant APP derivatives (the AB isoforms prone to aggregation) enter the mitochondria and disrupt the ETC, thereby generating free radicals [7]. Evidence for this chain of reasoning is that γ secretase, which is needed to cleave APP, is found inside the mitochondria. This suggests that after full length APP enter the mitochondria, they are cleaved there, upon which they may interfere with the mitochondrial proteins [7]. Another possible explanation for the damage to mitochondria was demonstrated by another study which indicated that accumulation of APP blocks mitochondrial protein transport channels, also contributing to mitochondrial dysfunction [4]. 

Conclusion: the Mitochondrial Cascade Hypothesis

Given the mitochondria’s crucial role in the maintenance of cellular bioenergetics, the organelle is likely a critical aspect of numerous facets of neurodegeneration, which are still under research. An emerging “mitochondrial cascade hypothesis,” seeks to highlight the importance of mitochondria in AD pathology. It ties together the various ways in which mitochondrial dysfunction is linked to the cascade of degenerative processes that occur in AD, all of which we have discussed so far. As higher ROS production rates lead to an accumulation of mitochondrial DNA damage, this decreases the ETC’s efficiency, which reduces overall oxidative phosphorylation and increases ROS production. This augmentation of ROS production triggers AB production from APP, leading to increased AB (and therefore amyloid plaques) which in turn also reduce ETC activity. Meanwhile, decreased oxidative phosphorylation and energy production in these neurons results in apoptosis, which in the large scale creates atrophy [6]. As Alzheimer’s is one of many neurodegenerative diseases with no cure, further research into the mitochondrial cascade hypothesis has the potential to expand the limited therapeutics available to treat the disease so far. 

 

References:

  1. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G. Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochimica et Biophysica Acta (BBA). 1802(1): 2-10. doi:10.1016/j.bbadis.2009.10.006.
  2. Parker WD, Parks J, Filley CM, Kleinschmidt-DeMasters BK. 1994. Electron transport chain defects in Alzheimer’s disease brain. Neurology. 44(6):1090-6. doi: 10.1212/wnl.44.6.1090.
  3. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA.2001. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci. 21(9):3017-23. doi: 10.1523/JNEUROSCI.21-09-03017.2001. 
  4. Anandatheerthavarada HK, Biswas G, Robin M, Avadhani NG. 2003. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol. 161(1): 41–54. doi:10.1083/jcb.200207030
  5. Wang X, Wang W, LI L, Perry G, Lee H, Zhu X. 2014. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochimica et Biophysica Acta (BBA). 1842(8):1240-1247. doi:10.1016/j.bbadis.2013.10.015.
  6. Swerdlow RS, Khan SM. 2008. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Medical Hypotheses. 63(1): 8-20. doi:10.1016/j.mehy.2003.12.045.
  7. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. 2006. Mitochondria are a direct site of Aβ accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Human Molecular Genetics. 15(9):1437–1449.doi:10.1093/hmg/ddl066
  8. Reddy PH, Beal MF. 2007. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med. 14(2):45-53. doi: 10.1016/j.molmed.2007.12.002.
  9. Coskun PE, Beal MF, Wallace DC. 2004. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 101(29):10726-31. doi:10.1073/pnas.0403649101
  10. Gabuzda A, Busciglio J, Chen LB, Matsudaira P, Yankner BA. 1994. Inhibition of Energy Metabolism Alters the Processing of Amyloid Precursor Protein and Induces a Potentially Amyloidogenic Derivative. J Biol Chem. 269(18): 13623-13628.