Mitophagy Modulation, a New Player in the Race against ALS

Madruga, Enrique López; Maestro, Inés; Martı́nez, Ana

doi:10.3390/ijms22020740

Cited by 31 publications

(35 citation statements)

References 116 publications

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“…With advancing age, autophagy gradually subsides and this decline is linked to defective mitochondria and results in inflammaging [189]. Damaged cellular and organelle components that accumulate as a result of inadequate autophagy are released as damage-associated molecular patterns (DAMPs) [190][191][192]. Dysfunctional mitochondria that are not eliminated by mitophagy release large amounts of mitochondrial DNA (mtDNA) into the cytosol and, together with ROS [193,194], metabolites such as ATP, fatty acids, Aβ, succinate, per-oxidized lipids, advanced glycation end-products, altered N-glycans, and HMGB1 are also recognized as DAMPs and trigger an innate immune inflammatory response [195,196] by directly activating TLR9.…”

Section: Defective Autophagy and Neuroinflammationmentioning

confidence: 99%

Neuroinflammation in Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

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Section: Defective Autophagy and Neuroinflammationmentioning

confidence: 99%

Neuroinflammation in Alzheimer’s Disease

et al. 2021

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“…The mitochondrial defect that causes energy deficiency in neurons is a major pathological feature of most neurodegenerative diseases and has been extensively reviewed recently (Monzio Compagnoni et al, 2020 ; Yan et al, 2020 ; Goyal and Chaturvedi, 2021 ; Johnson et al, 2021 ; Lee et al, 2021 ; Madruga et al, 2021 ; Nakagawa and Yamada, 2021 ). We have previously reviewed the evidence linking metabolic impairment and mitochondrial defect in neurodegenerative diseases (Liu and Chern, 2015 ; Liu et al, 2017 ).…”

Section: Impaired Translational Control Resulting From Energy Dysfunction In Neurodegenerative Diseasesmentioning

confidence: 99%

“…Recent studies also showed that motor neurons derived from iPSCs of C9orf72 -ALS patients have inferior mitochondrial bioenergetic functions, poor calcium buffering ability, and shorter axons (Dafinca et al, 2020 ; Mehta et al, 2021 ). Collectively, mitochondrial defects and the resultant defective energy metabolism is believed to be a major driver that plays a critical role in ALS pathogenesis and was extensively discussed in recent reviews (Calió et al, 2020 ; Dafinca et al, 2021 ; Jhanji et al, 2021 ; Madruga et al, 2021 ; Nakagawa and Yamada, 2021 ). The possible role of energy deficiency and AMPK activation in the impairment of protein translation in ALS warrants further research.…”

Section: Impaired Translational Control Resulting From Energy Dysfunction In Neurodegenerative Diseasesmentioning

confidence: 99%

Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases

Liu

Chern

2021

Front. Cell. Neurosci.

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Impaired energy homeostasis and aberrant translational control have independently been implicated in the pathogenesis of neurodegenerative diseases. AMP kinase (AMPK), regulated by the ratio of cellular AMP and ATP, is a major gatekeeper for cellular energy homeostasis. Abnormal regulation of AMPK has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Most importantly, AMPK activation is known to suppress the translational machinery by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1), activating translational regulators, and phosphorylating nuclear transporter factors. In this review, we describe recent findings on the emerging role of protein translation impairment caused by energy dysregulation in neurodegenerative diseases.

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“…Accordingly, within the last years, different autophagy modulators, including rapamycin, trehalose or rilmenidine, have been tested. However, they provided mixed results depending on the model used, administration route, and off-target effects ( Madruga et al, 2021 ), highlighting both the complexity and heterogeneity of this disease. Finally, targeting cytosolic Ca 2+ levels might be an additional promising approach, considering the low Ca 2+ buffering capacity and the high risk of glutamate induced excitotoxicity for vulnerable spinal motor neurons innervating fast-twitch muscles.…”

Section: Discussionmentioning

confidence: 99%

Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus

Paß

Wiesner

Pla‐Martín

2021

Front. Mol. Biosci.

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Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca2+ handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in rare neurological disorders, including Huntington’s disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.

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Mitophagy Modulation, a New Player in the Race against ALS

Cited by 31 publications

References 116 publications

Neuroinflammation in Alzheimer’s Disease

Neuroinflammation in Alzheimer’s Disease

Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases

Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus

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