scholarly journals The Mitochondrial RNA Granule is Necessary for Parkinsonism-Associated Metal Toxicity

2022 ◽  
Author(s):  
Erica Werner ◽  
Avanti Gokhale ◽  
Molly Ackert ◽  
Chongchong Xu ◽  
Zhexing Wen ◽  
...  
Keyword(s):  
Metal Toxicity ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Respiratory Chain ◽  
Protective Mechanism ◽  
Mitochondrial Rna ◽  
Molecular Systems ◽  
Manganese Exposure ◽  
Transcript Processing ◽  
And Function ◽  
Adult Drosophila

Manganese exposure causes a parkinsonian disorder, manganism, which is viewed as a neurodegenerative disorder minimally related to Parkinson s disease. We tested this hypothesis asking if there is phenotypic and mechanistic overlap between two genetic models of these diseases. We targeted for study the plasma membrane manganese efflux transporter SLC30A10 and the mitochondrial Parkinson gene PARK2. We performed comparative molecular systems studies and found that SLC30A10 and PARK2 mutations compromised the mitochondrial RNA granule as well as mitochondrial transcript processing. These shared RNA granule defects led to impaired assembly and function of the mitochondrial respiratory chain. Notably, CRISPR gene editing of subunits of the mitochondrial RNA granule, FASTKD2 and DHX30, or pharmacological inhibition of mitochondrial transcription-translation were protective rather than deleterious for survival of cells acutely exposed to manganese. Similarly, adult Drosophila mutants with defects in the mitochondrial RNA granule component scully were safeguarded from manganese-induced mortality. We conclude that the downregulation of the mitochondrial RNA granule function is a protective mechanism for acute metal toxicity. We propose that initially adaptive mitochondrial dysfunction caused by manganese exposure, when protracted, causes neurodegeneration

scholarly journals Cardiometabolism as an Interlocking Puzzle between the Healthy and Diseased Heart: New Frontiers in Therapeutic Applications

2021 ◽  
Vol 10 (4) ◽  
pp. 721
Author(s):  
Teresa Pasqua ◽  
Carmine Rocca ◽  
Anita Giglio ◽  
Tommaso Angelone
Keyword(s):  
Cardiac Muscle ◽  
Metabolic Networks ◽  
Mechanical Energy ◽  
Cardiac Metabolism ◽  
Protective Mechanism ◽  
Enzymatic Reactions ◽  
Carbohydrate Utilization ◽  
Pharmacological Agents ◽  
Physiological Structure ◽  
And Function

Cardiac metabolism represents a crucial and essential connecting bridge between the healthy and diseased heart. The cardiac muscle, which may be considered an omnivore organ with regard to the energy substrate utilization, under physiological conditions mainly draws energy by fatty acids oxidation. Within cardiomyocytes and their mitochondria, through well-concerted enzymatic reactions, substrates converge on the production of ATP, the basic chemical energy that cardiac muscle converts into mechanical energy, i.e., contraction. When a perturbation of homeostasis occurs, such as an ischemic event, the heart is forced to switch its fatty acid-based metabolism to the carbohydrate utilization as a protective mechanism that allows the maintenance of its key role within the whole organism. Consequently, the flexibility of the cardiac metabolic networks deeply influences the ability of the heart to respond, by adapting to pathophysiological changes. The aim of the present review is to summarize the main metabolic changes detectable in the heart under acute and chronic cardiac pathologies, analyzing possible therapeutic targets to be used. On this basis, cardiometabolism can be described as a crucial mechanism in keeping the physiological structure and function of the heart; furthermore, it can be considered a promising goal for future pharmacological agents able to appropriately modulate the rate-limiting steps of heart metabolic pathways.

scholarly journals Biogenesis of NDUFS3-less complex I indicates TMEM126A/OPA7 as an assembly factor of the ND4-module

2020 ◽  
Author(s):  
Luigi D’Angelo ◽  
Elisa Astro ◽  
Monica De Luise ◽  
Ivana Kurelac ◽  
Nikkitha Umesh-Ganesh ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Optic Atrophy ◽  
Complex I ◽  
Disease Gene ◽  
Mitochondrial Respiratory Chain ◽  
Cell Types ◽  
Catalytic Core ◽  
Assembly Factor ◽  
Functional Consequences ◽  
And Function

ABSTRACTComplex I (CI) is the largest enzyme of the mitochondrial respiratory chain and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyzed the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We prove that in diverse mammalian cell types a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we have determined the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion where the ND4-module remains stable and bound to TMEM126A. We have thus, uncovered the function of TMEM126A, the product of a disease gene causing recessive optic atrophy, as a factor necessary for the correct assembly and function of CI.

scholarly journals Ovarian Tumor Mitochondria Exhibit Abnormal Phenotypes and Blunted Associations with Biobehavioral Factors

2021 ◽  
Author(s):  
Snehal Bindra ◽  
Marlon McGill ◽  
Marina Triplett ◽  
Anisha Tyagi ◽  
Premal Thaker ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Respiratory Chain ◽  
Ovarian Tissue ◽  
Mitochondrial Respiratory Chain ◽  
Ovarian Tumors ◽  
Mitochondrial Content ◽  
Benign Tissue ◽  
Mitochondrial Respiratory Chain Activity ◽  
Respiratory Chain Activity ◽  
And Function

Abstract Tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and tumor mitochondria remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign and cancerous ovarian tissue in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n=1,435) showed that gene expression of specific mitochondrial proteins in ovarian tumors is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in 51 benign and 128 high-grade epithelial ovarian tumors revealed that compared to benign tissue, tumors exhibit 3.3-8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P<0.001) but similar mitochondrial DNA levels (-3.1%), documenting abnormal mitochondrial phenotypes in tumors. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r=-0.43 to 0.47). In contrast, serous tumors showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in ovarian tumors and warrant further research on the link between biobehavioral factors and mitochondria in cancer.

scholarly journals Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapy for Alzheimer’s Disease: Progress and Opportunity

Membranes ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 796
Author(s):  
Yi-An Chen ◽  
Cheng-Hsiu Lu ◽  
Chien-Chih Ke ◽  
Ren-Shyan Liu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Synaptic Loss ◽  
Molecular Machinery ◽  
And Function ◽  
Preclinical And Clinical Studies ◽  
Ad Therapy

Alzheimer’s disease (AD), as a neurodegenerative disorder, is characterized by mass neuronal and synaptic loss and, currently, there are no successful curative therapies. Extracellular vesicles (EVs) are an emerging approach to intercellular communication via transferring cellular materials such as proteins, lipids, mRNAs, and miRNAs from parental cells to recipient cells, leading to the reprogramming of the molecular machinery. Numerous studies have suggested the therapeutic potential of EVs derived from mesenchymal stem cells (MSCs) in the treatment of AD, based on the neuroprotective, regenerative and immunomodulatory effects as effective as MSCs. In this review, we focus on the biology and function of EVs, the potential of MSC-derived EVs for AD therapy in preclinical and clinical studies, as well as the potent mechanisms of MSC-derived EVs actions. Finally, we highlight the modification strategies and diagnosis utilities in order to make advance in this field.

scholarly journals Novel Role of ATPase Subunit C Targeting Peptides Beyond Mitochondrial Protein Import

2010 ◽  
Vol 21 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Cristofol Vives-Bauza ◽  
Jordi Magrané ◽  
Antoni L. Andreu ◽  
Giovanni Manfredi
Keyword(s):  
Respiratory Chain ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Genetic Redundancy ◽  
Mitochondrial Protein Import ◽  
Atpase Subunit ◽  
Subunit C ◽  
And Function

In mammals, subunit c of the F1F0-ATP synthase has three isoforms (P1, P2, and P3). These isoforms differ by their cleavable mitochondrial targeting peptides, whereas the mature peptides are identical. To investigate this apparent genetic redundancy, we knocked down each of the three subunit c isoform by RNA interference in HeLa cells. Silencing any of the subunit c isoforms individually resulted in an ATP synthesis defect, indicating that these isoforms are not functionally redundant. We found that subunit c knockdown impaired the structure and function of the mitochondrial respiratory chain. In particular, P2 silencing caused defective cytochrome oxidase assembly and function. Because the expression of exogenous P1 or P2 was able to rescue the respective silencing phenotypes, but the two isoforms were unable to cross-complement, we hypothesized that their functional specificity resided in their targeting peptides. In fact, the expression of P1 and P2 targeting peptides fused to GFP variants rescued the ATP synthesis and respiratory chain defects in the silenced cells. Our results demonstrate that the subunit c isoforms are nonredundant, because they differ functionally by their targeting peptides, which, in addition to mediating mitochondrial protein import, play a yet undiscovered role in respiratory chain maintenance.

scholarly journals Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo

2019 ◽  
Vol 28 (21) ◽  
pp. 3584-3599 ◽  
Author(s):  
Matthew G Williamson ◽  
Mattéa J Finelli ◽  
James N Sleigh ◽  
Amy Reddington ◽  
David Gordon ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Gene Encoding ◽  
Over Expression ◽  
Neuromuscular Abnormalities ◽  
And Function ◽  
Lateral Sclerosis

Abstract A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.

scholarly journals The MscS and MscL Families of Mechanosensitive Channels Act as Microbial Emergency Release Valves

2012 ◽  
Vol 194 (18) ◽  
pp. 4802-4809 ◽  
Author(s):  
Ian R. Booth ◽  
Paul Blount
Keyword(s):  
Structure And Function ◽  
Mechanosensitive Channel ◽  
Protective Mechanism ◽  
Mechanosensitive Channels ◽  
Additional Pressure ◽  
Environmental Extremes ◽  
Life Threatening ◽  
And Function ◽  
Compare And Contrast ◽  
Plant Organelles

ABSTRACTSingle-celled organisms must survive exposure to environmental extremes. Perhaps one of the most variable and potentially life-threatening changes that can occur is that of a rapid and acute decrease in external osmolarity. This easily translates into several atmospheres of additional pressure that can build up within the cell. Without a protective mechanism against such pressures, the cell will lyse. Hence, most microbes appear to possess members of one or both families of bacterial mechanosensitive channels, MscS and MscL, which can act as biological emergency release valves that allow cytoplasmic solutes to be jettisoned rapidly from the cell. While this is undoubtedly a function of these proteins, the discovery of the presence of MscS homologues in plant organelles and MscL in fungus and mycoplasma genomes may complicate this simplistic interpretation of the physiology underlying these proteins. Here we compare and contrast these two mechanosensitive channel families, discuss their potential physiological roles, and review some of the most relevant data that underlie the current models for their structure and function.

scholarly journals Integration of plastids with their hosts: Lessons learned from dinoflagellates

2015 ◽  
Vol 112 (33) ◽  
pp. 10247-10254 ◽  
Author(s):  
Richard G. Dorrell ◽  
Christopher J. Howe
Keyword(s):  
Lessons Learned ◽  
Plastid Evolution ◽  
Transcript Processing ◽  
And Function ◽  
Host Nucleus

After their endosymbiotic acquisition, plastids become intimately connected with the biology of their host. For example, genes essential for plastid function may be relocated from the genomes of plastids to the host nucleus, and pathways may evolve within the host to support the plastid. In this review, we consider the different degrees of integration observed in dinoflagellates and their associated plastids, which have been acquired through multiple different endosymbiotic events. Most dinoflagellate species possess plastids that contain the pigment peridinin and show extreme reduction and integration with the host biology. In some species, these plastids have been replaced through serial endosymbiosis with plastids derived from a different phylogenetic derivation, of which some have become intimately connected with the biology of the host whereas others have not. We discuss in particular the evolution of the fucoxanthin-containing dinoflagellates, which have adapted pathways retained from the ancestral peridinin plastid symbiosis for transcript processing in their current, serially acquired plastids. Finally, we consider why such a diversity of different degrees of integration between host and plastid is observed in different dinoflagellates and how dinoflagellates may thus inform our broader understanding of plastid evolution and function.

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