scholarly journals Amyloid-Beta Interaction with Mitochondria

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Lucia Pagani ◽  
Anne Eckert
Keyword(s):  
Mitochondrial Dysfunction ◽  
Amyloid Beta ◽  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Intracellular Localization ◽  
Protein A ◽  
Postmortem Brain ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane

Mitochondrial dysfunction is a hallmark of amyloid-beta(Aβ)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of Aβand its precursor protein (AβPP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial Aβmay directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both Aβand AβPP addressing the question of how Aβcan access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that Aβtriggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species (ROS) production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. In particular, we focus on Aβinteraction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix. Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

scholarly journals Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling

2020 ◽  
Author(s):  
Mustafa N. Okur ◽  
Evandro F. Fang ◽  
Elayne M. Fivenson ◽  
Vinod Tiwari ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Excision Repair ◽  
Mitochondrial Dynamics ◽  
Accelerated Aging ◽  
Cockayne Syndrome ◽  
Premature Aging ◽  
Postmortem Brain ◽  
Average Life Expectancy ◽  
Postmortem Brain Tissue ◽  
Genes Encoding

AbstractBackgroundCockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematodes and CS patients are not fully known.ResultsOur cross-species transcriptomic analysis in CS postmortem brain tissue, CS mouse and nematode models show that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with NAD+ supplementation.ConclusionsOur study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together these three agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.

scholarly journals Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak

2021 ◽  
Vol 9 ◽  
Author(s):  
Pooja Patel ◽  
Arielys Mendoza ◽  
Dexter J. Robichaux ◽  
Meng C. Wang ◽  
Xander H. T. Wehrens ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Family Member ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Inner Mitochondrial Membrane ◽  
Retention Capacity

Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death. Contrary to the role of Bax and Bak in apoptosis, which is dependent on their oligomerization, MPTP-dependent necrosis does not require oligomerization as monomeric/inactive forms of Bax and Bak can facilitate mitochondrial dysfunction. However, the relationship between Bax and Bak activation/oligomerization and MPTP sensitization remains to be explored. Here, we use a combination of in vitro and ex vivo approaches to determine the role of the anti-apoptotic Bcl-2 family members, which regulate Bax/Bak activity, in necrotic cell death and MPTP sensitivity. To study the role of each predominantly expressed anti-apoptotic Bcl-2 family member (i.e., Mcl-1, Bcl-2, and Bcl-xL) in MPTP regulation, we utilize various BH3 mimetics that specifically bind to and inhibit each. We determined that the inhibition of each anti-apoptotic Bcl-2 family member lowers mitochondrial calcium retention capacity and sensitizes MPTP opening. Furthermore, the inhibition of each Bcl-2 family member exacerbates both apoptotic and necrotic cell death in vitro in a Bax/Bak-dependent manner. Our findings suggests that mitochondrial Ca2+ retention capacity and MPTP sensitivity is influenced by Bax/Bak activation/oligomerization on the outer mitochondrial membrane, providing further evidence of the crosstalk between the apoptotic and necrotic cell death pathways.

scholarly journals Membrane-tethering of cytochrome c accelerates regulated cell death in yeast

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Alexandra Toth ◽  
Andreas Aufschnaiter ◽  
Olga Fedotovskaya ◽  
Hannah Dawitz ◽  
Pia Ädelroth ◽  
...  
Keyword(s):  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Membrane ◽  
Mitochondrial Respiratory Chain ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Fitness Advantage ◽  
Regulated Cell Death ◽  
Membrane Tethering ◽  
Membrane Anchoring

Abstract Intrinsic apoptosis as a modality of regulated cell death is intimately linked to permeabilization of the outer mitochondrial membrane and subsequent release of the protein cytochrome c into the cytosol, where it can participate in caspase activation via apoptosome formation. Interestingly, cytochrome c release is an ancient feature of regulated cell death even in unicellular eukaryotes that do not contain an apoptosome. Therefore, it was speculated that cytochrome c release might have an additional, more fundamental role for cell death signalling, because its absence from mitochondria disrupts oxidative phosphorylation. Here, we permanently anchored cytochrome c with a transmembrane segment to the inner mitochondrial membrane of the yeast Saccharomyces cerevisiae, thereby inhibiting its release from mitochondria during regulated cell death. This cytochrome c retains respiratory growth and correct assembly of mitochondrial respiratory chain supercomplexes. However, membrane anchoring leads to a sensitisation to acetic acid-induced cell death and increased oxidative stress, a compensatory elevation of cellular oxygen-consumption in aged cells and a decreased chronological lifespan. We therefore conclude that loss of cytochrome c from mitochondria during regulated cell death and the subsequent disruption of oxidative phosphorylation is not required for efficient execution of cell death in yeast, and that mobility of cytochrome c within the mitochondrial intermembrane space confers a fitness advantage that overcomes a potential role in regulated cell death signalling in the absence of an apoptosome.

Abstract 15070: Micu1 Regulates Mitochondrial Cristae Structure and Function Independent of the Mitochondrial Calcium Uniporter Channel

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dhanendra Tomar ◽  
Manfred Thomas ◽  
Joanne Garbincius ◽  
Devin Kolmetzky ◽  
Oniel Salik ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Coiled Coil ◽  
Structure And Function ◽  
Membrane Dynamics ◽  
Size Exclusion ◽  
Null Mouse ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Cytochrome C Release ◽  
And Function

Background: MICU1 is an EF-hand domain containing Ca 2+ -sensor regulating the mitochondrial Ca 2+ uniporter channel and mitochondrial Ca 2+ uptake. MICU1-null mouse and fly models display perinatal lethality with disorganized mitochondrial architecture. Interestingly, these phenotypes are distinct from other mtCU loss-of-function models ( MCU, MICU2, EMRE, MCUR1 ) and thus are likely not explained solely by changes in matrix Ca 2+ content. Using size-exclusion proteomics and co-immunofluorescence, we found that MICU1 localizes to mitochondrial complexes lacking MCU. These observations suggest that MICU1 may have additional cellular functions independent of the MCU. Methods: Biotin-based proximity labeling and proteomics, protein biochemistry, live-cell Ca 2+ imaging, electron microscopy, confocal and super-resolution imaging were utilized to identify and validate MICU1 novel functions. Results: The expression of a MICU1-BioID2 fusion protein in MCU +/+ and MCU -/- cells allowed the identification of the total vs. MCU-independent MICU1 interactome. LC-MS analysis of purified biotinylated proteins identified the mitochondrial contact site and cristae organizing system (MICOS) components Mitofilin (MIC60) and Coiled-coil-helix-coiled-coil helix domain containing 2 (CHCHD2) as MCU independent novel MICU1 interactors. We demonstrate that MICU1 is essential for proper organization of the MICOS complex and that MICU1 ablation results in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, membrane potential, and cell death signaling. We hypothesize that MICU1 is a MICOS Ca 2+ - sensor since perturbing MICU1 is sufficient to modulate cytochrome c release independent of Ca 2+ uptake across the inner mitochondrial membrane. Conclusions: Here, we provide the first experimental evidence of an intermembrane space Ca 2+ - sensor regulating mitochondrial membrane dynamics, independent of changes in matrix Ca 2+ content. This study provides a novel paradigm to understand Ca 2+ -dependent regulation of mitochondrial structure and function and may help explain the mitochondrial remodeling reported to occur in numerous disease states.

scholarly journals Mitochondrial dynamics: overview of molecular mechanisms

2018 ◽  
Vol 62 (3) ◽  
pp. 341-360 ◽  
Author(s):  
Lisa Tilokani ◽  
Shun Nagashima ◽  
Vincent Paupe ◽  
Julien Prudent
Keyword(s):  
Membrane Fusion ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Calcium Influx ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Membrane Lipid ◽  
Inner Mitochondrial Membrane ◽  
Step Process ◽  
Shape Distribution

Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.

scholarly journals Role of cytochrome c heme lyase in mitochondrial import and accumulation of cytochrome c in Saccharomyces cerevisiae.

1991 ◽  
Vol 11 (11) ◽  
pp. 5487-5496 ◽  
Author(s):  
M E Dumont ◽  
T S Cardillo ◽  
M K Hayes ◽  
F Sherman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cytochrome C ◽  
Mitochondrial Membrane ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Apocytochrome C ◽  
Cytochrome C Heme Lyase

Heme is covalently attached to cytochrome c by the enzyme cytochrome c heme lyase. To test whether heme attachment is required for import of cytochrome c into mitochondria in vivo, antibodies to cytochrome c have been used to assay the distributions of apo- and holocytochromes c in the cytoplasm and mitochondria from various strains of the yeast Saccharomyces cerevisiae. Strains lacking heme lyase accumulate apocytochrome c in the cytoplasm. Similar cytoplasmic accumulation is observed for an altered apocytochrome c in which serine residues were substituted for the two cysteine residues that normally serve as sites of heme attachment, even in the presence of normal levels of heme lyase. However, detectable amounts of this altered apocytochrome c are also found inside mitochondria. The level of internalized altered apocytochrome c is decreased in a strain that completely lacks heme lyase and is greatly increased in a strain that overexpresses heme lyase. Antibodies recognizing heme lyase were used to demonstrate that the enzyme is found on the outer surface of the inner mitochondrial membrane and is not enriched at sites of contact between the inner and outer mitochondrial membranes. These results suggest that apocytochrome c is transported across the outer mitochondrial membrane by a freely reversible process, binds to heme lyase in the intermembrane space, and is then trapped inside mitochondria by an irreversible conversion to holocytochrome c accompanied by folding to the native conformation. Altered apocytochrome c lacking the ability to have heme covalently attached accumulates in mitochondria only to the extent that it remains bound to heme lyase.

Stimulation of apoptosis by sulindac and piroxicam

1998 ◽  
Vol 95 (3) ◽  
pp. 385-388 ◽  
Author(s):  
William R. WADDELL
Keyword(s):  
Acetic Acid ◽  
Mitochondrial Membrane ◽  
Prostaglandin Synthesis ◽  
Intermembrane Space ◽  
Colon Polyps ◽  
Inner Mitochondrial Membrane ◽  
Normal Cells ◽  
Inhibition Of Prostaglandin Synthesis ◽  
Stimulation Of

1.Sulindac, cis-5-fluoro-2-methyl-1-(p-methylsulphinylbenzylidene)indene-3-acetic acid, inhibits growth of colon polyps and cancers. This effect has been attributed to inhibition of prostaglandin synthesis but more recent observations indicate that, in vitro, cells that do not have cyclo-oxygenase nor RNA for synthesis of such enzymes are affected by sulindac. Therefore the presumptive effect is probably not correct. 2.It has also been found that sulindac stimulates apoptosis. It is herein postulated that in tumour cells such effects may be due to interaction of the anionic form of the drug with protons in the intermembrane space of mitochondria to disrupt the potential across the inner mitochondrial membrane and thereby initiate apoptosis. Normal cells are not affected.

scholarly journals Kill one or kill the many: interplay between mitophagy and apoptosis

2020 ◽  
Vol 402 (1) ◽  
pp. 73-88
Author(s):  
Simone Wanderoy ◽  
J. Tabitha Hees ◽  
Ramona Klesse ◽  
Frank Edlich ◽  
Angelika B. Harbauer
Keyword(s):  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Special Focus ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Caspase Activation ◽  
The Central Nervous System ◽  
Mitochondrial Intermembrane Space ◽  
Specialized Form ◽  
The Many

AbstractMitochondria are key players of cellular metabolism, Ca2+ homeostasis, and apoptosis. The functionality of mitochondria is tightly regulated, and dysfunctional mitochondria are removed via mitophagy, a specialized form of autophagy that is compromised in hereditary forms of Parkinson’s disease. Through mitophagy, cells are able to cope with mitochondrial stress until the damage becomes too great, which leads to the activation of pro-apoptotic BCL-2 family proteins located on the outer mitochondrial membrane. Active pro-apoptotic BCL-2 proteins facilitate the release of cytochrome c from the mitochondrial intermembrane space (IMS) into the cytosol, committing the cell to apoptosis by activating a cascade of cysteinyl-aspartate specific proteases (caspases). We are only beginning to understand how the choice between mitophagy and the activation of caspases is determined on the mitochondrial surface. Intriguingly in neurons, caspase activation also plays a non-apoptotic role in synaptic plasticity. Here we review the current knowledge on the interplay between mitophagy and caspase activation with a special focus on the central nervous system.

scholarly journals ROMO1 is essential for glucose coupling in the pancreatic β cell of male mice

2021 ◽  
Author(s):  
Lisa Wells ◽  
Caterina Iorio ◽  
Andy Cheuk-Him Ng ◽  
Courtney Reeks ◽  
Siu-Pok Yee ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Dynamics ◽  
Critical Role ◽  
Physiological Role ◽  
Glucose Sensing ◽  
Mitochondrial Fusion ◽  
Male Mice ◽  
Inner Mitochondrial Membrane ◽  
Β Cell ◽  
Respiratory Capacity

AbstractReactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses ROS and regulates mitochondrial dynamics 1. ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. How ROMO1 promotes mitochondrial fusion and its physiological role remain unclear. Here we show that ROMO1 is essential for embryonic development, as ROMO1-null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 that catalyze mitochondrial membrane fusion. Knockout of ROMO1 in adult pancreatic β cells results in impaired glucose homeostasis in male mice due to an insulin secretion defect resulting from impaired glucose sensing. Mitochondria in ROMO1 β cell KO cells were swollen and fragmented, consistent with a role for ROMO1 in mitochondrial fusion in vivo. While basal respiration was normal in ROMO1β cell KO islets, spare respiratory capacity was lost. Taken together, our data indicate that ROMO1 is required for nutrient coupling in the β cell and point to a critical role for spare respiratory capacity in the maintenance of euglycemia in males.

scholarly journals Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

2013 ◽  
Vol 305 (4) ◽  
pp. H459-H476 ◽  
Author(s):  
Emanuele Marzetti ◽  
Anna Csiszar ◽  
Debapriya Dutta ◽  
Gauthami Balagopal ◽  
Riccardo Calvani ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cardiovascular System ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Late Life ◽  
Age Related ◽  
Functional Consequences ◽  
Cardiovascular Aging ◽  
The Life Course

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD.

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