The Latest Articles on Mitochondrial dysfunction and Neurodegenerative Diseases

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on Mitochondrial dysfunction and Neurodegenerative Diseases.

Title: Fluorescence microscopic platforms imaging mitochondrial abnormalities in neurodegenerative diseases

Authors: Yicheng Wang, Pengwei Wang, Cong Li

Type: Review

Abstract:

Neurodegenerative diseases (NDs) are progressive disorders that cause the degeneration of neurons. Mitochondrial dysfunction is a common symptom in NDs and plays a crucial role in neuronal loss. Mitochondrial abnormalities can be observed in the early stages of NDs and evolve throughout disease progression. Visualizing mitochondrial abnormalities can help understand ND progression and develop new therapeutic strategies. Fluorescence microscopy is a powerful tool for dynamically imaging mitochondria due to its high sensitivity and spatiotemporal resolution. This review discusses the relationship between mitochondrial dysfunction and ND progression, potential biomarkers for imaging dysfunctional mitochondria, advances in fluorescence microscopy for detecting organelles, the performance of fluorescence probes in visualizing ND-associated mitochondria, and the challenges and opportunities for developing new generations of fluorescence imaging platforms for monitoring mitochondria in NDs.

Access this article: https://doi.org/10.1016/j.addr.2023.114841

Title: Role of SIRT3 in mitochondrial biology and its therapeutic implications in neurodegenerative disorders

Authors: Yogesh Mishra, Ravinder K Kaundal

Type: Review

Abstract:

Sirtuin 3 (SIRT3), a mitochondrial deacetylase expressed preferentially in high-metabolic-demand tissues including the brain, requires NAD+ as a cofactor for catalytic activity. It regulates various processes such as energy homeostasis, redox balance, mitochondrial quality control, mitochondrial unfolded protein response, biogenesis, dynamics and mitophagy by altering protein acetylation status. Reduced SIRT3 expression or activity causes hyperacetylation of hundreds of mitochondrial proteins, which has been linked with neurological abnormalities, neuro-excitotoxicity and neuronal cell death. A body of evidence has suggested, SIRT3 activation as a potential therapeutic modality for age-related brain abnormalities and neurodegenerative disorders.

Access this article: https://doi.org/10.1016/j.drudis.2023.103583

Title: LPS-induced mitochondrial dysfunction regulates innate immunity activation and α-synuclein oligomerization in Parkinson's disease

Authors: A. Raquel Esteves, Diana F. Silva, Diana F. Silva, Diana F. Silva, Diana F. Silva, Diana F. Silva

Type: Review

Abstract:  

Sporadic Parkinson's disease (sPD) is a complex multifactorial disorder which etiology remains elusive. Several mechanisms have been described to contribute to PD development namely mitochondrial dysfunction, activation of inflammatory pathways and the deposition of unfolded proteins such as α-synuclein. Our work shows for the first time that lipopolysaccharide (LPS)-induced activation of innate immunity requires a functional mitochondria and mimics PD pathology in cells. We found in primary mesencephalic neurons that LPS targeted the mitochondria and activated neuronal innate immune responses, which culminated with α-synuclein oligomerization. Moreover, in cybrid cell lines repopulated with mtDNA from sPD subjects with inherent mitochondrial dysfunction and NT2-Rho0 obtained by long-term ethidium bromide exposure, and so without a functional mitochondrial, LPS was not able to further activate innate immunity or increase α-synuclein aggregation.

Herein, we showed that mesencephalic neurons are able to activate innate immunity after LPS exposure and this pathway is dependent on mitochondria. Moreover, we disclose that α-synuclein over production is an innate immune response. Our data indicate that mitochondria provide the base for innate immunity activation in idiopathic PD.

Access this article: https://doi.org/10.1016/j.redox.2023.102714

Title: Novel insights into Parkin-mediated mitochondrial dysfunction and neuroinflammation in Parkinson's disease

Authors: Sandro L. Pereira, Dajana Grossmann, Dajana Grossmann, Andreas Hermann, Anne Grünewald

Type: Review

Abstract:

Mutations in PRKN cause the second most common genetic form of Parkinson's disease (PD)—a debilitating movement disorder that is on the rise due to population aging in the industrial world. PRKN codes for an E3 ubiquitin ligase that has been well established as a key regulator of mitophagy. Together with PTEN-induced kinase 1 (PINK1), Parkin controls the lysosomal degradation of depolarized mitochondria. But Parkin's functions go well beyond mitochondrial clearance: the versatile protein is involved in mitochondria-derived vesicle formation, cellular metabolism, calcium homeostasis, mitochondrial DNA maintenance, mitochondrial biogenesis, and apoptosis induction. Moreover, Parkin can act as a modulator of different inflammatory pathways. In the current review, we summarize the latest literature concerning the diverse roles of Parkin in maintaining a healthy mitochondrial pool. Moreover, we discuss how these recent discoveries may translate into personalized therapeutic approaches not only for PRKN-PD patients but also for a subset of idiopathic cases.

Access this article: https://doi.org/10.1016/j.conb.2023.102720

Title: Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS

Authors: Anna Fernàndez Bernal,

Type: Review

Abstract: 

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.

Access this article: https://doi.org/10.1016/j.bbadis.2023.166716