Mitoferrin-2 (MFRN2) Regulates the Electrogenic Mitochondrial Calcium Uniporter and Interacts Physically with MCU

Nieminen, Anna‐Liisa; Schwartz, Justin; Hung, Hsin-I; Blocker, E. Riley; Gooz, Monika; Lemasters, John J.

doi:10.1016/j.bpj.2013.11.3224

Cited by 7 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been revealed that mitoferrin-1 and 2 (Mfrn1 and 2) are localized on the inner membrane of mitochondria and may play an important role in Fe uptake into the mitochondria [ 42 , 44 , 45 ]. Furthermore, a very recent report has proposed that the mitochondrial calcium uniporter (mCU) may also transport Fe into mitochondria, while Mfrn2 serves to regulate mCU transport [ 46 ]. Interestingly, some recent studies have suggested that mCUs are also involved in brain and heart mitochondrial dysfunction under IO conditions [ 7 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

et al. 2020

View full text Add to dashboard Cite

Iron (Fe) plays an essential role in many physiological processes. Hereditary hemochromatosis or frequent blood transfusions often cause iron overload (IO), which can lead to cardiomyopathy and arrhythmias; however, the underlying mechanism is not well defined. In the present study, we assess the hypothesis that IO promotes arrhythmias via reactive oxygen species (ROS) production, mitochondrial membrane potential (∆Ψm) depolarization, and disruption of cytosolic Ca dynamics. In ventricular myocytes isolated from wild type (WT) mice, both cytosolic and mitochondrial Fe levels were elevated following perfusion with the Fe3+/8-hydroxyquinoline (8-HQ) complex. IO promoted mitochondrial superoxide generation (measured using MitoSOX Red) and induced the depolarization of the ΔΨm (measured using tetramethylrhodamine methyl ester, TMRM) in a dose-dependent manner. IO significantly increased the rate of Ca wave (CaW) formation measured in isolated ventricular myocytes using Fluo-4. Furthermore, in ex-vivo Langendorff-perfused hearts, IO increased arrhythmia scores as evaluated by ECG recordings under programmed S1-S2 stimulation protocols. We also carried out similar experiments in cyclophilin D knockout (CypD KO) mice in which the mitochondrial permeability transition pore (mPTP) opening is impaired. While comparable cytosolic and mitochondrial Fe load, mitochondrial ROS production, and depolarization of the ∆Ψm were observed in ventricular myocytes isolated from both WT and CypD KO mice, the rate of CaW formation in isolated cells and the arrhythmia scores in ex-vivo hearts were significantly lower in CypD KO mice compared to those observed in WT mice under conditions of IO. The mPTP inhibitor cyclosporine A (CsA, 1 µM) also exhibited a protective effect. In conclusion, our results suggest that IO induces mitochondrial ROS generation and ∆Ψm depolarization, thus opening the mPTP, thereby promoting CaWs and cardiac arrhythmias. Conversely, the inhibition of mPTP ameliorates the proarrhythmic effects of IO.

show abstract

Section: Discussionmentioning

confidence: 99%

Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

et al. 2020

View full text Add to dashboard Cite

show abstract

“…While Mfrn1expression is restricted to erythroid-lineage cells, Mfrn2 is expressed ubiquitously including in the heart. In addition, a very recent report has proposed that the mitochondrial calcium uniporter (mCU) may also transport iron into mitochondria, while Mfrn2 serves to regulate mCU transport [78]. Iron in the mitochondrion can then be utilized for 1) storage in mitochondrial ferritin (FtMt); 2) synthesis of iron-sulfur clusters (ISC); and 3) heme synthesis which is necessary for erythropoiesis and mitochondrial metabolism under normal physiological conditions [110].…”

Section: Proposed Mechanisms Involved In the Pathogenesis Of Iron mentioning

confidence: 99%

“…Lastly, it has been proposed that free iron is transported into cardiac mitochondria by mCU under iron overload conditions leading to increased mitochondrial ROS, membrane depolarization and swelling as well as mitochondrial dysfunction [61, 78, 120]. Therefore, mCU blockers ( i.e .…”

Section: Treatment For Iron Overload Cardiomyopathymentioning

confidence: 99%

Involvement of cytosolic and mitochondrial iron in iron overload cardiomyopathy: an update

et al. 2018

View full text Add to dashboard Cite

Iron overload cardiomyopathy (IOC) is a major cause of death in patients with diseases associated with chronic anemia such as thalassemia or sickle cell disease after chronic blood transfusions. Associated with iron overload conditions, there is excess free iron that enters cardiomyocytes through both L- and T-type calcium channels thereby resulting in increased reactive oxygen species being generated via Haber-Weiss and Fenton reactions. It is thought that an increase in reactive oxygen species contributes to high morbidity and mortality rates. Recent studies have, however, suggested that it is iron overload in mitochondria that contributes to cellular oxidative stress, mitochondrial damage, cardiac arrhythmias, as well as the development of cardiomyopathy. Iron chelators, antioxidants, and/or calcium channel blockers have been demonstrated to prevent and ameliorate cardiac dysfunction in animal models as well as in patients suffering from cardiac iron overload. Hence, either a mono-therapy or combination therapies with any of the aforementioned agents may serve as a novel treatment in iron-overload patients in the near future. In the present article, we review the mechanisms of cytosolic and/or mitochondrial iron load in the heart which may contribute synergistically or independently to the development of iron-associated cardiomyopathy. We also review available as well as potential future novel treatments.

show abstract

“…The MCU pore can also include a dominant negative form of the MCU subunit, called MCUb (Raffaello et al, 2013). Finally, several other mitochondrial proteins have been purported to interact with the MCU complex and potentially modulate its function (Chaudhuri et al, 2016; Hoffman et al, 2014; Nieminen et al, 2014; Paupe et al, 2015; Tomar et al, 2016; Zeng et al, 2018). This degree of regulation of MCU, along with the variability of modulator expression across tissues, implies that the activity of this complex is attuned specifically to cellular needs.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Ca²⁺influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

Hutto

Bisbach

Abbas

et al. 2019

Preprint

View full text Add to dashboard Cite

9Mitochondrial Ca 2+ regulates key cellular processes including cytosolic Ca 2+ signals, 10 energy production, and susceptibility to apoptosis. Photoreceptors are specialized 11 neurons that have extraordinarily high energy demands and rely on cytosolic Ca 2+ 12 signals for light adaptation and neurotransmission. Here we show that unlike other 13 neurons zebrafish cone photoreceptors express low levels of the mitochondrial Ca 2+ 14 uniporter (MCU), the channel that allows mitochondrial Ca 2+ entry. To determine why 15 MCU expression is kept low, we overexpressed MCU specifically in cones. This 16 increases mitochondrial [Ca 2+ ], causes faster cytosolic Ca 2+ clearance, and accelerates 17 photoresponse recovery. Moreover, flux through the citric acid cycle increases despite 18 dramatic changes in mitochondrial ultrastructure and localization. Remarkably, cones 19 survive this ongoing stress until late adulthood. Our findings demonstrate the 20 importance of tuning mitochondrial Ca 2+ influx to modulate physiological and metabolic 21 processes and reveal a novel directed movement of abnormal mitochondria in 22 photoreceptors. 23Mitochondrial Ca 2+ uptake is also involved in energetic output (Glancy and Balaban, 57 2012). Ca 2+ can regulate the activity of mitochondrial enzymes including pyruvate 58 dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase 59

show abstract

Mitoferrin-2 (MFRN2) Regulates the Electrogenic Mitochondrial Calcium Uniporter and Interacts Physically with MCU

Cited by 7 publications

References 0 publications

Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

Involvement of cytosolic and mitochondrial iron in iron overload cardiomyopathy: an update

Mitochondrial Ca²⁺influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

Contact Info

Product

Resources

About

Mitoferrin-2 (MFRN2) Regulates the Electrogenic Mitochondrial Calcium Uniporter and Interacts Physically with MCU

Cited by 7 publications

References 0 publications

Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

Involvement of cytosolic and mitochondrial iron in iron overload cardiomyopathy: an update

Mitochondrial Ca2+influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

Contact Info

Product

Resources

About

Mitochondrial Ca²⁺influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors