bims-mikwok 2023-05-28 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023–05–28
ten papers selected by
Avinash N. Mukkala, University of Toronto

Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases.
Mitochondrial Transplantation Preserves Myocardial Function and Viability in Pediatric and Neonatal Donation After Circulatory Death Pig Hearts.
Distinct effects of cardiac mitochondrial calcium uniporter inactivation via EMRE deletion in the short and long term.
Mitochondrial transplantation as a possible therapeutic option for sarcopenia.
Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy.
Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis.
Oxidization of optic atrophy 1 cysteines occurs during heart ischemia-reperfusion and amplifies cell death by oxidative stress.
Optogenetically engineered Ca2+ oscillation-mediated DRP1 activation promotes mitochondrial fission and cell death.
Divergent metabolic programmes control two populations of MAIT cells that protect the lung.
Reducing mitochondrial ribosomal gene expression does not alter metabolic health or lifespan in mice.

J Transl Med. 2023 May 25. 21(1): 347

Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases.

Mingchu Sun, Wenhua Jiang, Nan Mu, Zihui Zhang, Lu Yu, Heng Ma.

  Cardiovascular disease (CVD) is the leading cause of noncommunicable disease-related death worldwide, and effective therapeutic strategies against CVD are urgently needed. Mitochondria dysfunction involves in the onset and development of CVD. Nowadays, mitochondrial transplantation, an alternative treatment aimed at increasing mitochondrial number and improving mitochondrial function, has been emerged with great therapeutic potential. Substantial evidence indicates that mitochondrial transplantation improves cardiac function and outcomes in patients with CVD. Therefore, mitochondrial transplantation has profound implications in the prevention and treatment of CVD. Here, we review the mitochondrial abnormalities that occur in CVD and summarize the therapeutic strategies of mitochondrial transplantation for CVD.

Keywords:  Cardiovascular diseases; Ischemia reperfusion injury; Mitochondrial dysfunction; Mitochondrial transplantation; Therapy

DOI:  https://doi.org/10.1186/s12967-023-04203-6
J Thorac Cardiovasc Surg. 2023 May 19. pii: S0022-5223(23)00434-8. [Epub ahead of print]

Mitochondrial Transplantation Preserves Myocardial Function and Viability in Pediatric and Neonatal Donation After Circulatory Death Pig Hearts.

Victor S Alemany, Rio Nomoto, Mossab Y Saeed, Aybuke Celik, William L Regan, Gregory S Matte, Dominic P Recco, Sitaram M Emani, Pedro J Del Nido, James D McCully.

   OBJECTIVE: Mitochondrial transplantation has been shown to preserve myocardial function and viability in porcine DCD adult hearts. Herein, we investigate the efficacy of mitochondrial transplantation for the preservation of myocardial function and viability in neonatal and pediatric porcine DCD heart donation.
METHODS: Circulatory death was induced in neonatal and pediatric Yorkshire pigs by cessation of mechanical ventilation. Hearts underwent 20 or 36 min. of warm ischemia time (WIT), 10 min. of cold cardioplegic arrest and then were harvested for ex-situ heart perfusion (ESHP). Following 15 min. of ESHP, hearts received either vehicle (VEH) or vehicle containing isolated autologous mitochondria (MITO). A sham non-ischemic group (SHAM) did not undergo WIT mimicking donation after brain death (DBD) heart procurement. Hearts underwent 2 hr. each of unloaded and loaded ESHP perfusion.
RESULTS: Following 4 hr. ESHP perfusion, LVDP, dP/dt max, and fractional shortening were significantly decreased (P< 0.001) in DCD hearts receiving VEH compared to Sham hearts. In contrast, DCD hearts receiving MITO exhibited significantly preserved LVDP, dP/dt max, and fractional shortening (P<0.001 each vs VEH, not significant vs SHAM). Infarct size was significantly decreased in DCD hearts receiving MITO as compared to VEH (P< 0.001). Pediatric DCD hearts subjected to extended WIT demonstrated significantly preserved fractional shortening and significantly decreased infarct size with MITO (P< 0.01 each vs VEH).
CONCLUSIONS: Mitochondrial transplantation in neonatal and pediatric pig DCD heart donation significantly enhances the preservation of myocardial function and viability and mitigates against damage secondary to extended WIT.

Keywords:  Donation after circulatory death; Heart transplant; Ischemia; Mitochondrial transplantation; Neonatal; Pediatric

DOI:  https://doi.org/10.1016/j.jtcvs.2023.05.010
J Mol Cell Cardiol. 2023 May 23. pii: S0022-2828(23)00093-7. [Epub ahead of print]

Distinct effects of cardiac mitochondrial calcium uniporter inactivation via EMRE deletion in the short and long term.

Hector Chapoy Villanueva, Jae Hwi Sung, Jackie A Stevens, Michael J Zhang, Peyton M Nelson, Saahiti Denduluri, Feng Feng, Timothy D O'Connell, DeWayne Townsend, Julia C Liu.

  Transport of Ca2+ into mitochondria is thought to stimulate the production of ATP, a critical process in the heart's fight or flight response, but excess Ca2+ can trigger cell death. The mitochondrial Ca2+ uniporter complex is the primary route of Ca2+ transport into mitochondria, in which the channel-forming protein MCU and the regulatory protein EMRE are essential for activity. In previous studies, chronic Mcu or Emre deletion differ from acute cardiac Mcu deletion in response to adrenergic stimulation and ischemia/reperfusion (I/R) injury, despite equivalent inactivation of rapid mitochondrial Ca2+ uptake. To explore this discrepancy between chronic and acute loss of uniporter activity, we compared short-term and long-term Emre deletion using a novel conditional cardiac-specific, tamoxifen-inducible mouse model. After short-term Emre deletion (3 weeks post-tamoxifen) in adult mice, cardiac mitochondria were unable to take up Ca2+, had lower basal mitochondrial Ca2+ levels, and displayed attenuated Ca2+-induced ATP production and mPTP opening. Moreover, short-term EMRE loss blunted cardiac response to adrenergic stimulation and improved maintenance of cardiac function in an ex vivo I/R model. We then tested whether the long-term absence of EMRE (3 months post-tamoxifen) in adulthood would lead to distinct outcomes. After long-term Emre deletion, mitochondrial Ca2+ handling and function, as well as cardiac response to adrenergic stimulation, were similarly impaired as in short-term deletion. Interestingly, however, protection from I/R injury was lost in the long-term. These data suggest that several months without uniporter function are insufficient to restore bioenergetic response but are sufficient to restore susceptibility to I/R.

Keywords:  ATP; Calcium; Ischemia/reperfusion; Mitochondria; Mitochondrial calcium uniporter; Permeability transition pore

DOI:  https://doi.org/10.1016/j.yjmcc.2023.05.007
J Mol Med (Berl). 2023 May 20.

Mitochondrial transplantation as a possible therapeutic option for sarcopenia.

Ibrahim Turkel, Berkay Ozerklig, Merve Yılmaz, Oner Ulger, Gokhan Burcin Kubat, Meltem Tuncer.

  With advancing age, the skeletal muscle phenotype is characterized by a progressive loss of mass, strength, and quality. This phenomenon, known as sarcopenia, has a negative impact on quality of life and increases the risk of morbidity and mortality in older adults. Accumulating evidence suggests that damaged and dysfunctional mitochondria play a critical role in the pathogenesis of sarcopenia. Lifestyle modifications, such as physical activity, exercise, and nutrition, as well as medical interventions with therapeutic agents, are effective in the management of sarcopenia and offer solutions to maintain and improve skeletal muscle health. Although a great deal of effort has been devoted to the identification of the best treatment option, these strategies are not sufficient to overcome sarcopenia. Recently, it has been reported that mitochondrial transplantation may be a possible therapeutic approach for the treatment of mitochondria-related pathological conditions such as ischemia, liver toxicity, kidney injury, cancer, and non-alcoholic fatty liver disease. Given the role of mitochondria in the function and metabolism of skeletal muscle, mitochondrial transplantation may be a possible option for the treatment of sarcopenia. In this review, we summarize the definition and characteristics of sarcopenia and molecular mechanisms associated with mitochondria that are known to contribute to sarcopenia. We also discuss mitochondrial transplantation as a possible option. Despite the progress made in the field of mitochondrial transplantation, further studies are needed to elucidate the role of mitochondrial transplantation in sarcopenia. KEY MESSAGES: Sarcopenia is the progressive loss of skeletal muscle mass, strength, and quality. Although the specific mechanisms that lead to sarcopenia are not fully understood, mitochondria have been identified as a key factor in the development of sarcopenia. Damaged and dysfunctional mitochondria initiate various cellular mediators and signaling pathways, which largely contribute to the age-related loss of skeletal muscle mass and strength. Mitochondrial transplantation has been reported to be a possible option for the treatment/prevention of several diseases. Mitochondrial transplantation may be a possible therapeutic option for improving skeletal muscle health and treating sarcopenia. Mitochondrial transplantation as a possible treatment option for sarcopenia.

Keywords:  Mitochondrial dysfunction; Mitochondrial transplantation; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1007/s00109-023-02326-3
Circ Res. 2023 May 26.

Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy.

Mingming Tong, Risa Mukai, Satvik Mareedu, Peiyong Zhai, Shin-Ichi Oka, Chun-Yang Huang, Chiao-Po Hsu, Fawad A K Yousufzai, Luke Fritzky, Wataru Mizushima, Gopal J Babu, Junichi Sadoshima.

   RATIONALE: Obesity induces cardiomyopathy characterized by hypertrophy and diastolic dysfunction. Whereas mitophagy mediated through an Atg7-dependent mechanism serves as an essential mechanism to maintain mitochondrial quality during the initial development of obesity cardiomyopathy, Rab9-dependent alternative mitophagy takes over the role during the chronic phase. Although it has been postulated that DRP1 (dynamin-related protein 1)-mediated mitochondrial fission and consequent separation of the damaged portions of mitochondria are essential for mitophagy, the involvement of DRP1 in mitophagy remains controversial.
OBJECTIVE: We investigated whether endogenous DRP1 is essential in mediating the 2 forms of mitophagy during high-fat diet (HFD)-induced obesity cardiomyopathy and, if so, what the underlying mechanisms are.
METHODS AND RESULTS: Mice were fed either a normal diet or an HFD (60 kcal %fat). Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD consumption. The induction of mitophagy by HFD consumption was completely abolished in tamoxifen-inducible cardiac-specific Drp1knockout (Drp1 MCM) mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. The increase in LC3-dependent general autophagy and colocalization between LC3 and mitochondrial proteins was abolished in Drp1 MCM mice. Activation of alternative mitophagy was also completely abolished in Drp1 MCM mice during the chronic phase of HFD consumption. DRP1 was phosphorylated at Ser616, localized at the mitochondria-associated membranes, and associated with Rab9 and Fis1 only during the chronic, but not acute, phase of HFD consumption.
CONCLUSIONS: DRP1 is an essential factor in mitochondrial quality control during obesity cardiomyopathy that controls multiple forms of mitophagy. Although DRP1 regulates conventional mitophagy through a mitochondria-associated membrane-independent mechanism during the acute phase, it acts as a component of the mitophagy machinery at the mitochondria-associated membranes in alternative mitophagy during the chronic phase of HFD consumption.

Keywords:  diet, high-fat; mice, knockout; mitochondria; mitophagy; obesity cardiomyopathy

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.322512
Sci Adv. 2023 May 24. 9(21): eadg8156

Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis.

Giovanni Quarato, Luigi Mari, Nicholas J Barrows, Mao Yang, Sebastian Ruehl, Mark J Chen, Cliff S Guy, Jonathan Low, Taosheng Chen, Douglas R Green.

Degradation of defective mitochondria is an essential process to maintain cellular homeostasis and it is strictly regulated by the ubiquitin-proteasome system (UPS) and lysosomal activities. Here, using genome-wide CRISPR and small interference RNA screens, we identified a critical contribution of the lysosomal system in controlling aberrant induction of apoptosis following mitochondrial damage. After treatment with mitochondrial toxins, activation of the PINK1-Parkin axis triggered a BAX- and BAK-independent process of cytochrome c release from mitochondria followed by APAF1 and caspase 9-dependent apoptosis. This phenomenon was mediated by UPS-dependent outer mitochondrial membrane (OMM) degradation and was reversed using proteasome inhibitors. We found that the subsequent recruitment of the autophagy machinery to the OMM protected cells from apoptosis, mediating the lysosomal degradation of dysfunctional mitochondria. Our results underscore a major role of the autophagy machinery in counteracting aberrant noncanonical apoptosis and identified autophagy receptors as key elements in the regulation of this process.

DOI: https://doi.org/10.1126/sciadv.adg8156
Redox Biol. 2023 May 19. pii: S2213-2317(23)00156-8. [Epub ahead of print]63 102755

Oxidization of optic atrophy 1 cysteines occurs during heart ischemia-reperfusion and amplifies cell death by oxidative stress.

Martina Semenzato, Mark J Kohr, Charlotte Quirin, Roberta Menabò, Petra Alanova, Lukas Alan, Anna Pellattiero, Elizabeth Murphy, Fabio Di Lisa, Luca Scorrano.

During cardiac ischemia-reperfusion, excess reactive oxygen species can damage mitochondrial, cellular and organ function. Here we show that cysteine oxidation of the mitochondrial protein Opa1 contributes to mitochondrial damage and cell death caused by oxidative stress. Oxy-proteomics of ischemic-reperfused hearts reveal oxidation of the C-terminal C786 of Opa1 and treatment of perfused mouse hearts, adult cardiomyocytes, and fibroblasts with H2O2 leads to the formation of a reduction-sensitive ∼180 KDa Opa1 complex, distinct from the ∼270 KDa one antagonizing cristae remodeling. This Opa1 oxidation process is curtailed by mutation of C786 and of the other 3 Cys residues of its C-terminal domain (Opa1TetraCys). When reintroduced in Opa1-/- cells, Opa1TetraCys is not efficiently processed into short Opa1TetraCys and hence fails to fuse mitochondria. Unexpectedly, Opa1TetraCys restores mitochondrial ultrastructure in Opa1-/- cells and protects them from H2O2-induced mitochondrial depolarization, cristae remodeling, cytochrome c release and cell death. Thus, preventing the Opa1 oxidation occurring during cardiac ischemia-reperfusion reduces mitochondrial damage and cell death induced by oxidative stress independent of mitochondrial fusion.

DOI: https://doi.org/10.1016/j.redox.2023.102755
J Cell Sci. 2023 May 26. pii: jcs.260819. [Epub ahead of print]

Optogenetically engineered Ca2+ oscillation-mediated DRP1 activation promotes mitochondrial fission and cell death.

Yi-Shyun Lai, Cheng-Chi Chang, Yong-Yi Chen, Thi My Hang Nguyen, Jixuan Xu, Ying-Chi Chen, Yu-Fen Chang, Chia-Yih Wang, Pai-Sheng Chen, Shih-Chieh Lin, I-Chen Peng, Shaw-Jenq Tsai, Wen-Tai Chiu.

  Mitochondrial dynamics regulate the quality and morphology of mitochondria. Calcium (Ca2+) plays an important role in regulating mitochondrial function. Here, we investigated the effects of optogenetically engineered Ca2+ signaling on mitochondrial dynamics. More specifically, customized illumination conditions could trigger unique Ca2+ oscillation waves to trigger specific signaling pathways. In this study, we found that modulating Ca2+ oscillations by increasing the light frequency, intensity, and exposure time could drive mitochondria toward the fission state, mitochondrial dysfunction, autophagy, and cell death. Moreover, illumination triggered phosphorylation at the Ser616 residue, but not the Ser637 residue of the mitochondrial fission protein, dynamin-related protein 1 (DRP1), via the activation of Ca2+-dependent kinases, CaMKII, ERK, and CDK1. However, optogenetically engineered Ca2+ signaling did not activate calcineurin phosphatase to dephosphorylate DRP1 at Ser637. In addition, light illumination had no effect on the expression levels of the mitochondrial fusion proteins, mitofusin (MFN)-1 and MFN2.Taken together, this study provides an effective and innovative approach to altering Ca2+ signaling for controlling mitochondrial fission with a more precise resolution than pharmacological approaches in the temporal dimension.

Keywords:  Calcium oscillation; DRP1; Mitochondrial fission; Optogenetics

DOI:  https://doi.org/10.1242/jcs.260819
Nat Cell Biol. 2023 May 25.

Divergent metabolic programmes control two populations of MAIT cells that protect the lung.

Thomas Riffelmacher, Mallory Paynich Murray, Chantal Wientjens, Shilpi Chandra, Viankail Cedillo-Castelán, Ting-Fang Chou, Sara McArdle, Christopher Dillingham, Jordan Devereaux, Aaron Nilsen, Simon Brunel, David M Lewinsohn, Jeff Hasty, Gregory Seumois, Christopher A Benedict, Pandurangan Vijayanand, Mitchell Kronenberg.

Although mucosal-associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set, and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Here, following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127-Klrg1+ and CD127+Klrg1- antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue. These populations remained altered from steady state for months as stable, separate MAIT cell lineages with enhanced effector programmes and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic programme, which was critical for their maintenance and IL-17A synthesis. This programme was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded antigen independently and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccination and immunotherapies.

DOI: https://doi.org/10.1038/s41556-023-01152-6
Sci Rep. 2023 May 24. 13(1): 8391

Reducing mitochondrial ribosomal gene expression does not alter metabolic health or lifespan in mice.

Kim Reid, Eileen G Daniels, Goutham Vasam, Rashmi Kamble, Georges E Janssens, Iman M Hu, Alexander E Green, Riekelt H Houtkooper, Keir J Menzies.

Maintaining mitochondrial function is critical to an improved healthspan and lifespan. Introducing mild stress by inhibiting mitochondrial translation invokes the mitochondrial unfolded protein response (UPRmt) and increases lifespan in several animal models. Notably, lower mitochondrial ribosomal protein (MRP) expression also correlates with increased lifespan in a reference population of mice. In this study, we tested whether partially reducing the gene expression of a critical MRP, Mrpl54, reduced mitochondrial DNA-encoded protein content, induced the UPRmt, and affected lifespan or metabolic health using germline heterozygous Mrpl54 mice. Despite reduced Mrpl54 expression in multiple organs and a reduction in mitochondrial-encoded protein expression in myoblasts, we identified few significant differences between male or female Mrpl54+/- and wild type mice in initial body composition, respiratory parameters, energy intake and expenditure, or ambulatory motion. We also observed no differences in glucose or insulin tolerance, treadmill endurance, cold tolerance, heart rate, or blood pressure. There were no differences in median life expectancy or maximum lifespan. Overall, we demonstrate that genetic manipulation of Mrpl54 expression reduces mitochondrial-encoded protein content but is not sufficient to improve healthspan in otherwise healthy and unstressed mice.

DOI: https://doi.org/10.1038/s41598-023-35196-3