Fighting Parkinson’s disease: The return of the mitochondria

Zambrano, Kevin; Barba, Diego; Castillo, Karina; Noboa, Luis; Argueta-Zamora, Dariana; Robayo, Paola; Arizaga, Eduardo; Caicedo, Andrés; Gavilanes, Antonio W. D.

doi:10.1016/j.mito.2022.02.003

Cited by 28 publications

(29 citation statements)

References 91 publications

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“…We investigated the effect of omevaloxolone on mitochondrial parameters in order to assess the preliminary therapeutic potential of this compound in diseases involving mitochondrial dysfunction. In this study, we included a variety of primary fibroblasts representing a severe, fatal mitochondrial disease C1 (Saada et al, 2008), a milder mitochondrial disease affecting COX (Abu-Libdeh et al, 2017), and two recessive forms of PD, a common neurodegenerative disease, which has previously been linked to mitochondrial dysfunction and oxidative stress [reviewed in (Zambrano et al, 2022)]. In this preliminary study, we incubated the cells with omaveloxolone in a concentration that was previously reported for the in vitro FA studies (Abeti et al, 2015;Abeti et al, 2018) and examined six different parameters to assess different aspects of its effect on mitochondrial function.…”

Section: Resultsmentioning

confidence: 99%

Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects

Zighan

Arkadir

Douiev

et al. 2022

Front. Mol. Biosci.

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Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson’s disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient’s cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease.

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Section: Resultsmentioning

confidence: 99%

Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects

Zighan

Arkadir

Douiev

et al. 2022

Front. Mol. Biosci.

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“…DAergic neurons are particularly affected by OS-related injuries since they can generate large amounts of ROS as a metabolic by-product via metabolization of dopamine by MAO and via auto-oxidation [124]. OS is regularly stated as a hallmark feature of PD [125]. Indeed, several studies have demonstrated increased markers of oxidative damage along with decreased levels of antioxidants in the blood and CSF of PD patients, which was found to be linked with the Nrf2 pathway [126,127].…”

Section: Nrf2 In Parkinson's Diseasementioning

confidence: 99%

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

et al. 2022

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Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents.

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“…At the cellular level, PD is hallmarked by α-synuclein (SNCA, PARK1/4) accumulation and toxicity, the appearance of Lewy bodies (LBs) and Lewy neurites (LNs); oxidative stress; Ca 2+ , metal and lipid dyshomeostasis; and organelle dysfunction. The latter ranges from mitochondrial dysfunction to endolysosomal defects, as well as impaired functionality of the Golgi and ER stress (Bernal-Conde et al, 2019 ; Nguyen et al, 2019 ; Malpartida et al, 2021 ; Udayar et al, 2022 ; Zambrano et al, 2022 ). Interestingly, LBs and LNs also display lipid accumulation and a dense packaging of dysfunctional organelles, merged with membranous structures and filaments (Shahmoradian et al, 2019 ).…”

Section: Inter-organellar Membrane Contact Sites In Neurodegeneration...mentioning

confidence: 99%

Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

et al. 2022

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Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism are commonly observed in early preclinical stages of major NDs, including Parkinson's disease (PD) and Alzheimer's disease (AD). Among the multitude of underlying defective molecular mechanisms that have been suggested in the past decades, dysregulation of inter-organellar communication through the so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type of subcellular organelle, to date, most focus has been put on defective communication between the ER and mitochondria in NDs, given these compartments are critical in neuronal survival. Contributions of other MCSs, notably those with endolysosomes and lipid droplets are emerging, supported as well by genetic studies, identifying genes functionally involved in lysosomal homeostasis. In this review, we summarize the molecular identity of the organelle interactome in yeast and mammalian cells, and critically evaluate the evidence supporting the contribution of disturbed MCSs to the general disrupted inter-organellar homeostasis in NDs, taking PD and AD as major examples.

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Fighting Parkinson’s disease: The return of the mitochondria

Cited by 28 publications

References 91 publications

Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects

Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

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