Benzo(a)pyrene-induced mitochondrial dysfunction and cell death in p53-null Hep3B cells

Brassinin is a phytochemical derived from Chinese cabbage, a cruciferous vegetable. Brassinin has shown anticancer effects on prostate and colon cancer cells, among others. However, its mechanisms and effects on hepatocellular carcinoma (HCC) have not been elucidated yet. Our results confirmed that brassinin exerted antiproliferative effects by reducing proliferating cell nuclear antigen (PCNA) activity, a proliferation indicator and inducing cell cycle arrest in human HCC (Huh7 and Hep3B) cells. Brassinin also increased mitochondrial Ca2+ levels and depolarized the mitochondrial membrane in both Huh7 and Hep3B cells. Moreover, brassinin generated high amounts of reactive oxygen species (ROS) in both cell lines. The ROS scavenger N-acetyl-L-cysteine (NAC) inhibited this brassinin-induced ROS production. Brassinin also regulated the AKT and mitogen-activated protein kinases (MAPK) signaling pathways in Huh7 and Hep3B cells. Furthermore, co-administering brassinin and pharmacological inhibitors for JNK, ERK1/2 and P38 decreased cell proliferation in both HCC cell lines more than the pharmacological inhibitors alone. Collectively, our results demonstrated that brassinin exerts antiproliferative effects via mitochondrial dysfunction and MAPK pathway regulation on HCC cells.

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Relevance of mitochondrial dysfunction during Sorafenib-induced cell death in liver cancer cells. Role of oxidative and nitrogen reactive species

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.12.418 ◽

2021 ◽

Vol 165 ◽

pp. 54

Author(s):

Patricia de la Cruz-Ojeda ◽

M. Ángeles Rodríguez-Hernández ◽

Elena Navarro-Villarán ◽

Paloma Gallego ◽

Pavla Staňková ◽

...

Keyword(s):

Cell Death ◽

Liver Cancer ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Reactive Species ◽

Liver Cancer Cells ◽

Nitrogen Reactive Species

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Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

APOPTOSIS ◽

10.1007/s10495-021-01668-y ◽

2021 ◽

Author(s):

Michela Raimondi ◽

Fabrizio Fontana ◽

Monica Marzagalli ◽

Matteo Audano ◽

Giangiacomo Beretta ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Mitochondrial Dysfunction ◽

Atp Synthesis ◽

Melanoma Cells ◽

Human Melanoma ◽

Ros Generation ◽

Therapy Outcomes ◽

Human Melanoma Cells ◽

Oxphos Complex

Abstract Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

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Magneto Mitochondrial Dysfunction Mediated Cancer Cell Death Using Intracellular Magnetic Nano-Transducers

Biomaterials Science ◽

10.1039/d1bm00419k ◽

2021 ◽

Author(s):

Wooram Park ◽

Seok-Jo Kim ◽

Paul Cheresh ◽

Jeanho Yun ◽

Byeongdu Lee ◽

...

Keyword(s):

Cell Death ◽

Cancer Therapy ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Cancer Cell ◽

High Sensitivity ◽

Intrinsic Pathway ◽

Cancer Cell Death

Mitochondria are crucial regulators of the intrinsic pathway of cancer cell death. The high sensitivity of cancer cells to mitochondrial dysfunction offers opportunities for emerging targets in cancer therapy. Herein,...

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AIF3 splicing switch triggers neurodegeneration

Molecular Neurodegeneration ◽

10.1186/s13024-021-00442-7 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Shuiqiao Liu ◽

Mi Zhou ◽

Zhi Ruan ◽

Yanan Wang ◽

Calvin Chang ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Nuclear Translocation ◽

Chromatin Condensation ◽

Neuronal Cell ◽

Adult Brain ◽

Postmortem Brain ◽

Mitochondrial Functions

Abstract Background Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain. Methods AIF splicing induction in brain was determined by multiple approaches including 5′ RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration. Results We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2–4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice. Conclusions We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.

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Mitochondrial dysfunction: A crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain

Pharmacology Biochemistry and Behavior ◽

10.1016/j.pbb.2011.08.019 ◽

2011 ◽

Vol 100 (2) ◽

pp. 311-319 ◽

Cited By ~ 56

Author(s):

Pradeep K. Kamat ◽

Santoshkumar Tota ◽

Rakesh Shukla ◽

Shakir Ali ◽

Abul Kalam Najmi ◽

...

Keyword(s):

Cell Death ◽

Mitochondrial Dysfunction ◽

Rat Brain ◽

Okadaic Acid ◽

Memory Impairment ◽

Apoptotic Cell ◽

Apoptotic Cell Death

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Neuroprotective Effect of Nortriptyline in Overt Hepatic Encephalopathy Through Attenuation of Mitochondrial Dysfunction

ASN NEURO ◽

10.1177/1759091418810583 ◽

2018 ◽

Vol 10 ◽

pp. 175909141881058 ◽

Cited By ~ 3

Author(s):

Ji Heun Jeong ◽

Do Kyung Kim ◽

Nam-Seob Lee ◽

Young-Gil Jeong ◽

Ho Won Kim ◽

...

Keyword(s):

Cell Death ◽

Hepatic Encephalopathy ◽

Substantia Nigra ◽

Mitochondrial Dysfunction ◽

Mitochondrial Permeability Transition ◽

Neuroprotective Effect ◽

Motor Deficits ◽

Apoptotic Pathway ◽

Duct Ligation ◽

Overt Hepatic Encephalopathy

Hyperammonemia associated with overt hepatic encephalopathy (OHE) causes excitotoxic neuronal death through activation of the cytochrome C (CytC)-mediated mitochondria-dependent apoptotic pathway. We tested the therapeutic effect of nortriptyline (NT), a mitochondrial permeability transition pore (mPTP) blocker that can possibly inhibit mitochondrial CytC efflux to the cytosol on in vivo and in vitro OHE models. After ensuring the generation of OHE rats, established by bile duct ligation (BDL), they were intraperitoneally administered either 20 mg/kg NT (i.e., BDL+NT) or another vehicle (i.e., BDL+VEH) for 14 days. Compared with the control, BDL+VEH showed an increment of motor deficits, cell death, synaptic loss, apoptosis, and mitochondria with aberrant morphology in substantia nigra compacta dopaminergic (DA-ergic) neurons. However, the extent was significantly reversed in BDL+NT. Subsequently, we studied the neuroprotective mechanism of NT using PC-12 cells, a DA-ergic cell line, which exposed glutamate used as an excitotoxin. Compared with the control, the cells exposed to 15 mM glutamate (i.e., GLU) showed incremental cell death, apoptosis, and demise in mitochondrial respiration. Importantly, efflux of CytC from mitochondria to cytosol and the dissipation of mitochondrial membrane potential (△Ψm), an indicator of mPTP opening, were prominent in GLU. However, compared with the GLU, the cells cotreated with 10 μM NT (i.e., GLU+NT) showed a significant reduction in the aforementioned phenomenon. Together, we concluded that NT can be used for OHE therapeutics, mitigating the excitotoxic death of substantia nigra compacta DA-ergic neurons via mPTP-associated mitochondrial dysfunction inhibition.

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