Tracking intra‐ and inter‐organelle signaling of mitochondria

Madreiter‐Sokolowski, Corina T.; Ramadani‐Muja, Jeta; Ziomek, Gabriela; Burgstaller, Sandra; Bischof, Helmut; Koshenov, Zhanat; Gottschalk, Benjamin; Malli, Roland; Graier, Wolfgang F.

doi:10.1111/febs.15103

Cited by 27 publications

(13 citation statements)

References 238 publications

(281 reference statements)

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“…Mitochondria are the powerhouses providing most ATP for cells, and the high dynamic organelles as well 40 . Mitochondrial dynamics plays an important role in maintenance of mitochondrial mass and function, and is also involved in a variety of cellular activities including proliferation, migration and apoptosis 41 - 43 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells

Zou¹,

Yu²,

Shi³

et al. 2021

J. Cancer

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Cisplatin (DDP) is the first-line chemotherapeutic agent for ovarian cancer. However, the development of DDP resistance seriously influences the chemotherapeutic effect and prognosis of ovarian cancer. It was reported that DDP can directly impinge on the mitochondria and activate the intrinsic apoptotic pathway. Herein, the role of mitochondrial dynamics in DDP chemoresistance in human ovarian cancer SKOV3 cells was investigated. In DDP-resistant SKOV3/DDP cells, mitochondrial fission protein DRP1 was down-regulated, while mitochondrial fusion protein MFN2 was up-regulated. In accordance with the expression of DRP1 and MFN2, the average mitochondrial length was significantly increased in SKOV3/DDP cells. In DDP-sensitive parental SKOV3 cells, downregulation of DRP1 and upregulation of mitochondrial fusion proteins including MFN1,2 and OPA1 occurred at day 2~6 under cisplatin stress. Knockdown of DRP1 or overexpression of MFN2 promoted the resistance of SKOV3 cells to cisplatin. Intriguingly, weaker migration capability and lower ATP level were detected in SKOV3/DDP cells. Respective knockdown of DRP1 in parental SKOV3 cells or MFN2 in SKOV3/DDP cells using siRNA efficiently reversed mitochondrial dynamics, migration capability and ATP level. Moreover, MFN2 siRNA significantly aggravated the DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3/DDP cells. In contrast, DRP1 siRNA alleviated DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3 cells. Thus, these results indicate that mitochondrial dynamics mediated by DRP1 and MFN2 contributes to the development of DDP resistance in ovarian cancer cells, and will also provide a new strategy to prevent chemoresistance in ovarian cancer by targeting mitochondrial dynamics.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells

Zou¹,

Yu²,

Shi³

et al. 2021

J. Cancer

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“…While the outer mitochondrial membrane (OMM) is largely permeable to Ca 2+ via the voltage-dependent anion channel (VDAC), Ca 2+ transport across the inner mitochondrial membrane (IMM) is highly restricted. High Ca 2+ concentrations within the MAM regions allow unblocking the gatekeeper proteins mitochondrial Ca 2+ uptake 1 and 2 (MICU1 and MICU2) and the Ca 2+ uptake via the mitochondrial Ca 2+ uniporter (MCU), controlled by a variety of proteins [ 49 ]. This protein complex includes, among others, the essential MCU regulator (EMRE) linking MICU1 and MICU2 to MCU [ 50 ], the scaffold factor MCU regulator 1 (MCUR1) [ 51 ], the dominant-negative pore-forming subunit MCUb [ 52 ] and the mitochondrial Ca 2+ uptake 3 (MICU3) acting as enhancer of MCU-dependent mitochondrial Ca 2+ uptake [ 53 ].…”

Section: Ca 2+ Homeostasismentioning

confidence: 99%

Interrelation between ROS and Ca2+ in aging and age-related diseases

2020

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Calcium (Ca 2+ ) and reactive oxygen species (ROS) are versatile signaling molecules coordinating physiological and pathophysiological processes. While channels and pumps shuttle Ca 2+ ions between extracellular space, cytosol and cellular compartments, short-lived and highly reactive ROS are constantly generated by various production sites within the cell. Ca 2+ controls membrane potential, modulates mitochondrial adenosine triphosphate (ATP) production and affects proteins like calcineurin (CaN) or calmodulin (CaM), which, in turn, have a wide area of action. Overwhelming Ca 2+ levels within mitochondria efficiently induce and trigger cell death. In contrast, ROS comprise a diverse group of relatively unstable molecules with an odd number of electrons that abstract electrons from other molecules to gain stability. Depending on the type and produced amount, ROS act either as signaling molecules by affecting target proteins or as harmful oxidative stressors by damaging cellular components. Due to their wide range of actions, it is little wonder that Ca 2+ and ROS signaling pathways overlap and impact one another. Growing evidence suggests a crucial implication of this mutual interplay on the development and enhancement of age-related disorders, including cardiovascular and neurodegenerative diseases as well as cancer.

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“…Mitochondria can distribute throughout the cytoplasm (pancytoplasmic), subplasmalemmal, or perinuclear. Precise distributions are essential for energy supply (18, 19), the plasma membrane Ca 2+ channel activity (46), Ca 2+ signaling (47)(48)(49), and hypoxic state and signaling (26-29). Moreover, several reports demonstrate a closed relationship between mitochondrial motility and the mitochondria-ER tethering (50), Ca 2+ transport (51), and redox state (52,53).…”

Section: Discussionmentioning

confidence: 99%

Air plasma-activated medium exerts tumor-specific cytotoxicity via the oxidative stress-induced perinuclear mitochondrial clustering

Suzuki-Karasaki¹,

Ando²,

Ochiai³

et al. 2021

Preprint

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Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy eliminating cancers effectively and safely is the current clinical choice. Since aggressive tumors have inherent or acquired resistance to multidisciplinary therapies targeting apoptosis, tumor-specific induction of another cell death modality is a promising avenue to meet the goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can induce cell death in OS and OC via a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) because of the characteristic unipolar mitochondrial perinuclear aggregation. APAM had potent antitumor activity both in vitro and in vivo. APAM caused apoptosis, necrotic cell death, and autophagy. APAM contained hydrogen peroxide and increased mitochondrial ROS (mROS), while the antioxidant N-acetylcysteine (NAC) prevented cell death. MPMC occurred following mitochondrial fragmentation coinciding with nuclear damages. MPMC was accompanied by the tubulin network remodeling and mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC and the microtubule inhibitor, Nocodazole. Increased Cardiolipin (CL) oxidation was also seen, and NAC and the peroxy radical scavenger Ferrostatin-1 prevented it. In contrast, in fibroblasts, APAM induced minimal cell death, mROS generation, mLPO accumulation, CL oxidation, and MPMC. These results suggest that MPMC is a tumor-specific cause of cell death via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC might serve as a promising target for exerting tumor-specific cytotoxicity. Graphical abstract

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Tracking intra‐ and inter‐organelle signaling of mitochondria

Cited by 27 publications

References 238 publications

Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells

Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells

Interrelation between ROS and Ca2+ in aging and age-related diseases

Air plasma-activated medium exerts tumor-specific cytotoxicity via the oxidative stress-induced perinuclear mitochondrial clustering

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