Mitochondria-Shaping Proteins and Chemotherapy

The emergence, in recent decades, of an entirely new area of “Mitochondrial dynamics”, which consists principally of fission and fusion, reflects the recognition that mitochondria play a significant role in human tumorigenesis and response to therapeutics. Proteins that determine mitochondrial dynamics are referred to as “shaping proteins”. Marked heterogeneity has been observed in the response of tumor cells to chemotherapy, which is associated with imbalances in mitochondrial dynamics and function leading to adaptive and acquired resistance to chemotherapeutic agents. Therefore, targeting mitochondria-shaping proteins may prove to be a promising approach to treat chemotherapy resistant cancers. In this review, we summarize the alterations of mitochondrial dynamics in chemotherapeutic processing and the antitumor mechanisms by which chemotherapy drugs synergize with mitochondria-shaping proteins. These might shed light on new biomarkers for better prediction of cancer chemosensitivity and contribute to the exploitation of potent therapeutic strategies for the clinical treatment of cancers.

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Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Oncogene ◽

10.1038/s41388-021-01886-3 ◽

2021 ◽

Author(s):

Rósula García-Navas ◽

Pilar Liceras-Boillos ◽

Carmela Gómez ◽

Fernando C. Baltanás ◽

Nuria Calzada ◽

...

Keyword(s):

Mitochondrial Dynamics ◽

Redox Homeostasis ◽

Atp Production ◽

Oxidative Energy Metabolism ◽

Ras Activation ◽

Mitochondrial Defects ◽

Critical Requirement ◽

Dynamics And Function ◽

And Function ◽

And Control

AbstractSOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function.

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Does metformin modulate mitochondrial dynamics and function in type 2 diabetic patients?

Antioxidants and Redox Signaling ◽

10.1089/ars.2021.0019 ◽

2021 ◽

Author(s):

Aranzazu Martinez de Marañón ◽

Francisco Gerardo Canet ◽

Zaida Abad-Jimenez ◽

Ana Jover ◽

Carlos Morillas ◽

...

Keyword(s):

Mitochondrial Dynamics ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Dynamics And Function ◽

And Function ◽

Type 2 Diabetic

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Neuron-based high-content assay and screen for CNS active mitotherapeutics

Science Advances ◽

10.1126/sciadv.aaw8702 ◽

2020 ◽

Vol 6 (2) ◽

pp. eaaw8702 ◽

Cited By ~ 2

Author(s):

Boglarka H. Varkuti ◽

Miklos Kepiro ◽

Ze Liu ◽

Kyle Vick ◽

Yosef Avchalumov ◽

...

Keyword(s):

Small Molecule ◽

Hippocampal Neurons ◽

Mitochondrial Dynamics ◽

Synaptic Activity ◽

Glutamate Toxicity ◽

Primary Neurons ◽

Screening Assay ◽

Dynamics And Function ◽

Small Molecule Modulators ◽

And Function

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1–42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

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The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons

Human Molecular Genetics ◽

10.1093/hmg/ddt319 ◽

2013 ◽

Vol 22 (23) ◽

pp. 4706-4719 ◽

Cited By ~ 129

Author(s):

Wenzhang Wang ◽

Li Li ◽

Wen-Lang Lin ◽

Dennis W. Dickson ◽

Leonard Petrucelli ◽

...

Keyword(s):

Motor Neurons ◽

Mitochondrial Dynamics ◽

Dynamics And Function ◽

And Function

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Extracellular Matrix Proteins Modulate Antimigratory and Apoptotic Effects of Doxorubicin

Chemotherapy Research and Practice ◽

10.1155/2012/268681 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Georges Said ◽

Marie Guilbert ◽

Hamid Morjani ◽

Roselyne Garnotel ◽

Pierre Jeannesson ◽

...

Keyword(s):

Drug Resistance ◽

Tumor Cells ◽

Topoisomerase I ◽

Type I Collagen ◽

De Novo ◽

Acquired Resistance ◽

Chemotherapeutic Agents ◽

Type I ◽

Induced Apoptosis ◽

Apoptotic Effects

Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR). Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR). Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR). The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR).

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Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

Diabetes Obesity and Metabolism ◽

10.1111/dom.13497 ◽

2018 ◽

Vol 21 (1) ◽

pp. 146-159 ◽

Cited By ~ 13

Author(s):

Adi Drori ◽

Anna Permyakova ◽

Rivka Hadar ◽

Shiran Udi ◽

Alina Nemirovski ◽

...

Keyword(s):

Mitochondrial Dynamics ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Cannabinoid 1 Receptor ◽

Proximal Tubular ◽

Renal Proximal Tubular Cells ◽

Dynamics And Function ◽

Renal Proximal Tubular ◽

And Function

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Altered mitochondrial dynamics and function in APOE4-expressing astrocytes

Cell Death and Disease ◽

10.1038/s41419-020-02776-4 ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 2

Author(s):

Eran Schmukler ◽

Shira Solomon ◽

Shira Simonovitch ◽

Yona Goldshmit ◽

Eya Wolfson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Transgenic Mice ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Major Risk Factor ◽

Sporadic Alzheimer’S Disease ◽

Dynamics And Function ◽

And Function

Abstract APOE4 is a major risk factor for sporadic Alzheimer’s disease; however, it is unclear how it exerts its pathological effects. Others and we have previously shown that autophagy is impaired in APOE4 compared to APOE3 astrocytes, and demonstrated differences in the expression of mitochondrial dynamics proteins in brains of APOE3 and APOE4 transgenic mice. Here, we investigated the effect of APOE4 expression on several aspects of mitochondrial function and network dynamics, including fusion, fission, and mitophagy, specifically in astrocytes. We found that APOE3 and APOE4 astrocytes differ in their mitochondrial dynamics, suggesting that the mitochondria of APOE4 astrocytes exhibit reduced fission and mitophagy. APOE4 astrocytes also show impaired mitochondrial function. Importantly, the autophagy inducer rapamycin enhanced mitophagy and improved mitochondrial functioning in APOE4 astrocytes. Collectively, the results demonstrate that APOE4 expression is associated with altered mitochondrial dynamics, which might lead to impaired mitochondrial function in astrocytes. This, in turn, may contribute to the pathological effects of APOE4 in Alzheimer’s disease.

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