bims-midtic 2024-01-07 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2024‒01‒07
thirty papers selected by
Omkar Joshi, Turku Bioscience

Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif.
Role of mitochondrial fission in stress susceptibility.
Mitochondrial lipid dynamics regulated by MITOL-mediated ubiquitination.
Fission-independent compartmentalization of mitochondria during budding yeast cell division.
MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
Mitochondrial-derived vesicles in metabolism, disease, and aging.
Mitochondrial fusion-fission dynamics and its involvement in colorectal cancer.
SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.
Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
Mitochondrial outer membrane translocase MoTom20 modulates mitochondrial morphology and is important for infectious growth of the rice blast fungus.
The mitochondrial protease PARL is required for spermatogenesis.
3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.
Mitochondria as secretory organelles and therapeutic cargos.
The nascent polypeptide-associated complex subunit Egd1 is required for efficient selective mitochondrial degradation in budding yeast.
Relevance of the endoplasmic reticulum-mitochondria axis in cancer diagnosis and therapy.
VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.
The follicle-stimulating hormone triggers rapid changes in mitochondrial structure and function in porcine cumulus cells.
Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.
HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
Mitochondrial dynamics disruption: Unraveling Dinotefuran's impact on cardiotoxicity.
MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent Mechanism.
Alterations in mitochondria isolated from peripheral blood mononuclear cells and tumors of patients with epithelial ovarian cancers.
Mitochondria-derived reactive oxygen species are the likely primary trigger of mitochondrial retrograde signaling in Arabidopsis.
The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.
A long-wavelength mitochondria-targeted CO fluorescent probe for living cells and zebrafish imaging.
Mitochondrial density in skeletal and cardiac muscle.
Arginine-methylated c-Myc affects mitochondrial mitophagy in mouse acute kidney injury via Slc25a24.
The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography.
Melatonin enhances captopril mediated cardioprotective effects and improves mitochondrial dynamics in male Wistar rats with chronic heart failure.

Nat Commun. 2024 Jan 02. 15(1): 52

Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif.

Isabel Pérez-Jover, Kristy Rochon, Di Hu, Mukesh Mahajan, Pooja Madan Mohan, Isaac Santos-Pérez, Julene Ormaetxea Gisasola, Juan Manuel Martinez Galvez, Jon Agirre, Xin Qi, Jason A Mears, Anna V Shnyrova, Rajesh Ramachandran.

The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo. Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, surprisingly leading to the fission of model membranes in vitro. In vivo, the involvement of the native CT-SLiM is critical for productive mitochondrial and peroxisomal fission, as both deletion and non-native extension of the CT-SLiM severely impair their progression. Thus, contrary to prevailing models, Drp1-catalyzed membrane fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.

DOI: https://doi.org/10.1038/s41467-023-44413-6
Lab Anim (NY). 2024 Jan;53(1): 8

Role of mitochondrial fission in stress susceptibility.

Jorge Ferreira.

DOI: https://doi.org/10.1038/s41684-023-01311-0
J Biochem. 2023 Dec 29. pii: mvad117. [Epub ahead of print]

Mitochondrial lipid dynamics regulated by MITOL-mediated ubiquitination.

Koji Yamano, Hiroki Kinefuchi, Waka Kojima.

  Mitochondria-endoplasmic reticulum (ER) contact sites in mammals provide platforms for various reactions such as calcium signaling, lipid metabolism, organelle dynamics and autophagy. To fulfill these tasks, a number of proteins assemble at the contact sites including MITOL/MARCHF5, a critical mitochondrial ubiquitin ligase. How MITOL regulates mitochondrial function from the contact site, however, has been largely unresolved. Recently, a new role for MITOL in the active transport of phosphatidic acid from the ER to mitochondria was reported. In this commentary, we briefly summarize our current understanding of mitochondria-ER contact sites and discuss the recently elucidated mechanism of MITOL fine-tuning phospholipid transfer activity through ubiquitination.

Keywords:  contact site; mitochondria; phospholipid; ubiquitin; ubiquitin ligase

DOI:  https://doi.org/10.1093/jb/mvad117
J Cell Biol. 2024 Mar 04. pii: e202211048. [Epub ahead of print]223(3):

Fission-independent compartmentalization of mitochondria during budding yeast cell division.

Saori R Yoshii, Yves Barral.

Lateral diffusion barriers compartmentalize membranes to generate polarity or asymmetrically partition membrane-associated macromolecules. Budding yeasts assemble such barriers in the endoplasmic reticulum (ER) and the outer nuclear envelope at the bud neck to retain aging factors in the mother cell and generate naïve and rejuvenated daughter cells. However, little is known about whether other organelles are similarly compartmentalized. Here, we show that the membranes of mitochondria are laterally compartmentalized at the bud neck and near the cell poles. The barriers in the inner mitochondrial membrane are constitutive, whereas those in the outer membrane form in response to stresses. The strength of mitochondrial diffusion barriers is regulated positively by spatial cues from the septin axis and negatively by retrograde (RTG) signaling. These data indicate that mitochondria are compartmentalized in a fission-independent manner. We propose that these diffusion barriers promote mitochondrial polarity and contribute to mitochondrial quality control.

DOI: https://doi.org/10.1083/jcb.202211048
EMBO Rep. 2023 Dec 14.

MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.

Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, Atan Gross.

  Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.

Keywords:  LPA; MFN2; MTCH2; Mitochondria-ER Communication; Mitochondrial Fusion

DOI:  https://doi.org/10.1038/s44319-023-00009-1
Annu Rev Biophys. 2024 Jan 02.

Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.

Arun Kumar Kondadi, Andreas S Reichert.

Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling and immune responses. They are highly dynamic at different structural and functional levels. Mitochondria have been shown to constantly undergo fusion and fission processes and dynamically interact with other organelles such as the endoplasmic reticulum, peroxisomes, and lipid droplets. The field of mitochondrial dynamics has evolved hand in hand with technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling of the cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer of mitochondrial dynamics. In this review, we discuss mitochondrial dynamics at the following levels: (a) within an individual mitochondrion, (b) among mitochondria, and (c) between mitochondria and other organelles. Although the three tiers of mitochondrial dynamics have in the past been classified in a hierarchical manner, they are functionally connected and must act in a coordinated manner to maintain cellular functions and thus prevent various human diseases. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-biophys-030822-020736
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00446-1. [Epub ahead of print]36(1): 21-35

Mitochondrial-derived vesicles in metabolism, disease, and aging.

Tim König, Heidi M McBride.

Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.

DOI: https://doi.org/10.1016/j.cmet.2023.11.014
Mol Oncol. 2023 Dec 29.

Mitochondrial fusion-fission dynamics and its involvement in colorectal cancer.

Zihong Wu, Chong Xiao, Fang Li, Wenbo Huang, Fengming You, Xueke Li.

  The incidence and mortality rates of colorectal cancer have elevated its status as a significant public health concern. Recent research has elucidated the crucial role of mitochondrial fusion-fission dynamics in the initiation and progression of colorectal cancer. Elevated mitochondrial fission or fusion activity can contribute to the metabolic reprogramming of tumor cells, thereby activating oncogenic pathways that drive cell proliferation, invasion, migration, and drug resistance. Nevertheless, excessive mitochondrial fission can induce apoptosis, whereas moderate mitochondrial fusion can protect cells from oxidative stress. This imbalance in mitochondrial dynamics can exert dual roles as both promoters and inhibitors of colorectal cancer progression. This review provides an in-depth analysis of the fusion-fission dynamics and the underlying pathological mechanisms in colorectal cancer cells. Additionally, it offers partial insights into the mitochondrial kinetics in colorectal cancer-associated cells, such as immune and endothelial cells. This review is aimed at identifying key molecular events involved in colorectal cancer progression and highlighting the potential of mitochondrial dynamic proteins as emerging targets for pharmacological intervention.

Keywords:  Colorectal cancer; dynamics; mitochondrial fission; mitochondrial fusion; progression

DOI:  https://doi.org/10.1002/1878-0261.13578
Free Radic Biol Med. 2023 Dec 27. pii: S0891-5849(23)01184-X. [Epub ahead of print]212 220-233

SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.

Yu Song, Wen Geng, Dingchao Zhu, Huaizhen Liang, Zhi Du, Bide Tong, Kun Wang, Shuai Li, Yong Gao, Xiaobo Feng, Zhiwei Liao, Rongcheng Mei, Cao Yang.

  Nucleus pulposus (NP) cell function-loss is one main contributor during intervertebral disc degeneration (IDD) progression. Both mitochondria and endoplasmic reticulum (ER) play vital roles in sustaining NP cell homeostasis, while the precise function of ER-mitochondria tethering and cross talk in IDD remain to be clarified. Here, we demonstrated that a notable disruption of mitochondria-associated ER membrane (MAM) was identified in degenerated discs and TBHP-induced NP cells, accompanied by mitochondrial Zn2+ overload and NP cell senescence. Importantly, experimental coupling of MAM contacts by MFN2, a critical regulator of MAM formation, could enhance NLRX1-SLC39A7 complex formation and mitochondrial Zn2+ homeostasis. Further using the sequencing data from TBHP-induced degenerative model of NP cells, combining the reported MAM proteomes, we demonstrated that SYNJ2BP loss was one critical pathological characteristic of NP cell senescence and IDD progression, which showed close relationship with MAM disruption. Overexpression of SYNJ2BP could facilitate MAM contact organization and NLRX1-SLC39A7 complex formation, thus promoted mitochondrial Zn2+ homeostasis, NP cell proliferation and intervertebral disc rejuvenation. Collectively, our present study revealed a critical role of SYNJ2BP in maintaining mitochondrial Zn2+ homeostasis in NP cells during IDD progression, partially via sustaining MAM contact and NLRX1-SLC39A7 complex formation.

Keywords:  Intervertebral disc degeneration; Mitochondria-associated ER membrane; NLRX1; Nucleus pulposus; SLC39A7; SYNJ2BP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.028
Nat Commun. 2024 Jan 02. 15(1): 168

Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.

Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song, He He.

Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.

DOI: https://doi.org/10.1038/s41467-023-44057-6
Mol Plant Microbe Interact. 2024 Jan 03.

Mitochondrial outer membrane translocase MoTom20 modulates mitochondrial morphology and is important for infectious growth of the rice blast fungus.

Shuang Wu, Ying Zhang, Lele Xu, Haibo Zhang, Yuhe Li, Leiyun Yang, Zhengguang Zhang, Haifeng Zhang.

Mitochondria are highly dynamic organelles that constantly change their morphology to adapt the cellular environment through fission and fusion, which is critical for a cell to maintain normal cellular functions. Despite the significance of this process in the development and pathogenicity of the rice blast fungus Magnaporthe oryzae (M. oryzae), the underlying mechanism remains largely elusive. Here, we identified and characterized a mitochondrial outer membrane translocase MoTom20 in M. oryzae. Targeted gene deletion revealed that MoTom20 plays an important role in vegetative growth, conidiogenesis, penetration and infectious growth of M. oryzae. The growth rate, conidial production, appressorium turgor and pathogenicity are decreased in the ΔMotom20 mutant compared to that in the wild type and complemented strains. Further analysis revealed that MoTom20 localizes in mitochondrion and plays a key role in regulating mitochondrial fission and fusion balance which is critical for infectious growth. Finally, we found that MoTom20 is involved in fatty acid utilization and its yeast homolog ScTom20 is able to rescue the defects of ΔMotom20 in mitochondrial morphology and pathogenicity. Overall, our data demonstrate that MoTom20 is a key regulator for mitochondrial morphology maintenance which is important for infectious growth of the rice blast fungus.

DOI: https://doi.org/10.1094/MPMI-10-23-0168-R
Commun Biol. 2024 Jan 05. 7(1): 44

The mitochondrial protease PARL is required for spermatogenesis.

Sarah Schumacher, Laura Klose, Jessica Lambertz, Dieter Lütjohann, Ronald Biemann, Stefanie Kuerten, Lars Fester.

Mitochondrial function plays an important role in the maintenance of male fertility. However, the mechanisms underlying mitochondrial defect-related infertility remain mostly unclear. Here we show that a deficiency of PARL (Parl-/-), a mitochondrial protease, causes complete arrest of spermatogenesis during meiosis I. PARL deficiency led to severe downregulation of proteins of respiratory chain complex IV in testes that did not occur in other tested organs, causing a deficit in complex IV activity and ATP production. Furthermore, Parl-/- testes showed an almost complete loss of HSD17B3, a protein of the sER responsible for the last step in testosterone synthesis. While testosterone production appeared to be restored by overexpression of HSD17B12, loss of the canonical testosterone synthesis led to an upregulation of luteinizing hormone (LH) and of LH-regulated responses. These results suggest an important impact of the downstream regulation of mitochondrial defects that manifest in a cell-type-specific manner and extend beyond mitochondria.

DOI: https://doi.org/10.1038/s42003-023-05703-3
bioRxiv. 2023 Dec 14. pii: 2023.11.13.566502. [Epub ahead of print]

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.

Estevão Scudese, Zer Vue, Prassana Katti, Andrea Marshall, Larry Vang, Edgar Garza López, Kit Neikirk, Dominique Stephens, Duane D Hall, Rahmati Rostami, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine Wanjalla, Aaron Whiteside, Clintoria Williams, Steven M Damo, Jennifer A Gaddy, Annet Kirabo, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Vernat Exil, Bret C Mobley, Antentor Hinton.

Sarcopenia is an age-related loss of skeletal muscle, characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although mitochondrial aging is associated with decreased mitochondrial capacity, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging still requires further elucidation. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern these changes remain unclear. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. We found that mitochondria became less complex with age. Specifically, mitochondria lost surface area, complexity, and perimeter, indicating age-related declines in ATP synthesis and interaction capacity. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), which we show is required for mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved with Marf, the MFN2 ortholog in Drosophila , as Marf knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusins.

DOI: https://doi.org/10.1101/2023.11.13.566502
Exp Mol Med. 2024 Jan 04.

Mitochondria as secretory organelles and therapeutic cargos.

Joonho Suh, Yun-Sil Lee.

Mitochondria have been primarily considered intracellular organelles that are responsible for generating energy for cell survival. However, accumulating evidence suggests that mitochondria are secreted into the extracellular space under physiological and pathological conditions, and these secreted mitochondria play diverse roles by regulating metabolism, the immune response, or the differentiation/maturation in target cells. Furthermore, increasing amount of research shows the therapeutic effects of local or systemic administration of mitochondria in various disease models. These findings have led to growing interest in exploring mitochondria as potential therapeutic agents. Here, we discuss the emerging roles of mitochondria as extracellularly secreted organelles to shed light on their functions beyond energy production. Additionally, we provide information on therapeutic outcomes of mitochondrial transplantation in animal models of diseases and an update on ongoing clinical trials, underscoring the potential of using mitochondria as a novel therapeutic intervention.

DOI: https://doi.org/10.1038/s12276-023-01141-7
Sci Rep. 2024 Jan 04. 14(1): 546

The nascent polypeptide-associated complex subunit Egd1 is required for efficient selective mitochondrial degradation in budding yeast.

Yuan Tian, Koji Okamoto.

Selective degradation of dysfunctional or excess mitochondria is a fundamental process crucial for cell homeostasis in almost all eukaryotes. This process relies on autophagy, an intracellular self-eating system conserved from yeast to humans and is thus called mitophagy. Detailed mechanisms of mitophagy remain to be fully understood. Here we show that mitochondrial degradation in budding yeast, which requires the pro-mitophagic protein Atg32, is strongly reduced in cells lacking Egd1, a beta subunit of the nascent polypeptide-associated complex acting in cytosolic ribosome attachment and protein targeting to mitochondria. By contrast, loss of the sole alpha subunit Egd2 or the beta subunit paralogue Btt1 led to only a partial or slight reduction in mitophagy. We also found that phosphorylation of Atg32, a crucial step for priming mitophagy, is decreased in the absence of Egd1. Forced Atg32 hyperphosphorylation almost completely restored mitophagy in egd1-null cells. Together, we propose that Egd1 acts in Atg32 phosphorylation to facilitate mitophagy.

DOI: https://doi.org/10.1038/s41598-023-50245-7
Exp Mol Med. 2024 Jan 04.

Relevance of the endoplasmic reticulum-mitochondria axis in cancer diagnosis and therapy.

Garam An, Junho Park, Jisoo Song, Taeyeon Hong, Gwonhwa Song, Whasun Lim.

Dynamic interactions between organelles are responsible for a variety of intercellular functions, and the endoplasmic reticulum (ER)-mitochondrial axis is recognized as a representative interorganelle system. Several studies have confirmed that most proteins in the physically tethered sites between the ER and mitochondria, called mitochondria-associated ER membranes (MAMs), are vital for intracellular physiology. MAM proteins are involved in the regulation of calcium homeostasis, lipid metabolism, and mitochondrial dynamics and are associated with processes related to intracellular stress conditions, such as oxidative stress and unfolded protein responses. Accumulating evidence has shown that, owing to their extensive involvement in cellular homeostasis, alterations in the ER-mitochondrial axis are one of the etiological factors of tumors. An in-depth understanding of MAM proteins and their impact on cell physiology, particularly in cancers, may help elucidate their potential as diagnostic and therapeutic targets for cancers. For example, the modulation of MAM proteins is utilized not only to target diverse intracellular signaling pathways within cancer cells but also to increase the sensitivity of cancer cells to anticancer reagents and regulate immune cell activities. Therefore, the current review summarizes and discusses recent advances in research on the functional roles of MAM proteins and their characteristics in cancers from a diagnostic perspective. Additionally, this review provides insights into diverse therapeutic strategies that target MAM proteins in various cancer types.

DOI: https://doi.org/10.1038/s12276-023-01137-3
Nat Commun. 2024 Jan 04. 15(1): 205

VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.

Ojasee Bapat, Tejas Purimetla, Sarah Kruessel, Monil Shah, Ruolin Fan, Christina Thum, Fiona Rupprecht, Julian D Langer, Vidhya Rangaraju.

Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.

DOI: https://doi.org/10.1038/s41467-023-44233-8
Sci Rep. 2024 Jan 03. 14(1): 436

The follicle-stimulating hormone triggers rapid changes in mitochondrial structure and function in porcine cumulus cells.

Amel Lounas, Yann Breton, Ariane Lebrun, Isabelle Laflamme, Nathalie Vernoux, Julie Savage, Marie-Ève Tremblay, Martin Pelletier, Marc Germain, François J Richard.

Oocyte maturation is a key process during which the female germ cell undergoes resumption of meiosis and completes its preparation for embryonic development including cytoplasmic and epigenetic maturation. The cumulus cells directly surrounding the oocyte are involved in this process by transferring essential metabolites, such as pyruvate, to the oocyte. This process is controlled by cyclic adenosine monophosphate (cAMP)-dependent mechanisms recruited downstream of follicle-stimulating hormone (FSH) signaling in cumulus cells. As mitochondria have a critical but poorly understood contribution to this process, we defined the effects of FSH and high cAMP concentrations on mitochondrial dynamics and function in porcine cumulus cells. During in vitro maturation (IVM) of cumulus-oocyte complexes (COCs), we observed an FSH-dependent mitochondrial elongation shortly after stimulation that led to mitochondrial fragmentation 24 h later. Importantly, mitochondrial elongation was accompanied by decreased mitochondrial activity and a switch to glycolysis. During a pre-IVM culture step increasing intracellular cAMP, mitochondrial fragmentation was prevented. Altogether, the results demonstrate that FSH triggers rapid changes in mitochondrial structure and function in COCs involving cAMP.

DOI: https://doi.org/10.1038/s41598-023-50586-3
Mol Cell Biochem. 2023 Dec 29.

Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.

Da Huo, Xin-Yu Bi, Jun-Ling Zeng, Da-Mao Dai, Xiang-Lin Dong.

  Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-β)/Notch interaction via small mothers against decapentaplegic 3 (Smad3) could facilitate HS formation; therefore, targeting TGF-β/ Notch interaction via Smad3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-β/Smad3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-β/Notch interaction via Smad3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-β pathway, Notch pathway, and TGF-β/Notch interaction via Smad3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-β/Notch interaction via Smad3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-β/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-β/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation.

Keywords:  DAPT; Hypertrophic scar formation; Mitochondrial fusion; Pirfenidone; SIS3; TGF-β/Notch interaction

DOI:  https://doi.org/10.1007/s11010-023-04912-y
Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2306454120

HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.

Mengying Cui, Koji Yamano, Kenichi Yamamoto, Hitomi Yamamoto-Imoto, Satoshi Minami, Takeshi Yamamoto, Sho Matsui, Tatsuya Kaminishi, Takayuki Shima, Monami Ogura, Megumi Tsuchiya, Kohei Nishino, Brian T Layden, Hisakazu Kato, Hidesato Ogawa, Shinya Oki, Yukinori Okada, Yoshitaka Isaka, Hidetaka Kosako, Noriyuki Matsuda, Tamotsu Yoshimori, Shuhei Nakamura.

  Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation-qPCR, we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB-HKDC1 axis was essential for PINK1 (PTEN-induced kinase 1)/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels, with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and maintaining mitochondria-lysosome contact. Interestingly, HKDC1 regulated mitophagy and lysosomal repair independently of its prospective function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage-induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.

Keywords:  HKDC1; TFEB; cellular senescence; mitochondria–lysosome contact; mitophagy

DOI:  https://doi.org/10.1073/pnas.2306454120
Environ Pollut. 2023 Dec 28. pii: S0269-7491(23)02240-6. [Epub ahead of print]343 123238

Mitochondrial dynamics disruption: Unraveling Dinotefuran's impact on cardiotoxicity.

Jiaping Zhu, Qiao Tao, Gaoyi Du, Lei Huang, Meng Li, Mengcen Wang, Qiangwei Wang.

  Exposure to pesticides has been associated with several cardiovascular complications in animal models. Neonicotinoids are now the most widely used insecticide globally, while the impact of neonicotinoids on cardiovascular function and the role of mitochondrial dynamics in neonicotinoids-induced cardiotoxicity is unclear. In the present study, Xenopus laevis tadpoles were exposed to environmental related concentrations (0, 5, and 50 μg/L) of typical neonicotinoid dinotefuran, with two enantiomers, for 21 days. We evaluated the changes in heart rate and cardiomyocyte apoptosis in exposed tadpoles. Then, we performed the transcriptome, metabolomics, transmission electron microscopy (TEM), and protein immunoblot to investigate the potential adverse impact of two enantiomers of dinotefuran on cardiotoxicity associated with mitochondrial dynamics. We observed changes in heart rate and increased cardiomyocyte apoptosis in exposed tadpoles, indicating that dinotefuran had a cardiotoxic effect. We further found that the cardiac contractile function pathway was significantly enriched, while the glucose metabolism-related pathways were also disturbed significantly. TEM observation revealed that the mitochondrial morphology of cardiomyocytes in exposed tadpoles was swollen, and mitophagy was increased. Mitochondria fusion was excessively manifested in the enhanced mitochondrial fusion protein. The mitochondrial respiratory chain was also disturbed, which led to an increase in ROS production and a decrease in ATP content. Therefore, our results suggested that dinotefuran exposure can induce cardiac disease associated mitochondrial disorders by interfering with the functionality and dynamics of mitochondria. In addition, both two enantiomers of dinotefuran have certain toxicity to tadpole cardiomyocytes, while R-dinotefuran exhibited higher toxicity than S-enantiomer, which may be attributed to disparities in the activation capacities of the respiratory chain.

Keywords:  Cardiotoxicity; Dinotefuran; Mitochondrial dynamics; Mitochondrial dysfunction; Xenopus laevis

DOI:  https://doi.org/10.1016/j.envpol.2023.123238
Int J Biol Sci. 2024 ;20(2): 569-584

MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent Mechanism.

Shanshan Liu, Shuai Han, Cuili Wang, Hongjun Chen, Qiannan Xu, Shi Feng, Yucheng Wang, Jihong Yao, Qin Zhou, Xuanli Tang, Li Lin, Lidan Hu, Alan J Davidson, Bing Yang, Cunqi Ye, Fan Yang, Jianhua Mao, Chao Tong, Jianghua Chen, Hong Jiang.

  Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Mitochondrial dysfunction in renal tubules, occurring early in the disease, is linked to the development of DKD, although the underlying pathways remain unclear. Here, we examine diabetic human and mouse kidneys, and HK-2 cells exposed to high glucose, to show that high glucose disrupts mitochondria-associated endoplasmic reticulum membrane (MAM) and causes mitochondrial fragmentation. We find that high glucose conditions increase mitogen-activated protein kinase 1(MAPK1), a member of the MAP kinase signal transduction pathway, which in turn lowers the level of phosphofurin acidic cluster sorting protein 2 (PACS-2), a key component of MAM that tethers mitochondria to the ER. MAPK1-induced disruption of MAM leads to mitochondrial fragmentation but this can be rescued in HK-2 cells by increasing PACS-2 levels. Functional studies in diabetic mice show that inhibition of MAPK1 increases PACS-2 and protects against the loss of MAM and the mitochondrial fragmentation. Taken together, these results identify the MAPK1-PACS-2 axis as a key pathway to therapeutically target as well as provide new insights into the pathogenesis of DKD.

Keywords:  MAPK1; PACS-2; diabetic kidney disease; mitochondria; mitochondria-associated endoplasmic reticulum membrane

DOI:  https://doi.org/10.7150/ijbs.89291
Sci Rep. 2024 01 02. 14(1): 15

Alterations in mitochondria isolated from peripheral blood mononuclear cells and tumors of patients with epithelial ovarian cancers.

Kittipat Charoenkwan, Nattayaporn Apaijai, Sirawit Sriwichaiin, Nipon Chattipakorn, Siriporn C Chattipakorn.

Metabolic alterations play an essential role in ovarian carcinogenesis. The flexibility of mitochondrial functions facilitates cellular adaptation to the tough environment associated with carcinogenesis. An understanding of the differences in mitochondrial functions in normal ovaries and cancers could provide a basis for further exploration of future mitochondria-based screening, diagnosis, prognostic prediction, and targeted therapy for epithelial ovarian cancers. The main objective of this study was to assess mitochondrial function profiles measured from PBMCs and ovarian tissues of epithelial ovarian cancers in comparison with normal ovaries. A total of 36 patients were recruited for the study, all of whom underwent primary surgical treatment for malignant epithelial ovarian neoplasm. Of these, 20 patients were in the early stage and 16 patients were in the advanced stage. Additionally, 21 patients who had pelvic surgery for benign gynecologic conditions, with normal ovaries incidentally removed, were recruited as controls. At the time of surgery, a blood sample was collected from each participant for PBMC isolation, and ovarian tissue was retained for molecular studies. These studies included the examination of oxidative stress, mitochondrial mass, mitochondrial respiration, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes, and mitochondrial swelling. Clinical and histopathological data were also collected and compared between different stages of epithelial ovarian cancers: early-stage (group 1), advanced-stage (group 2), and normal ovaries (group 3). The levels of cellular oxidative stress, mitochondrial mass, and mitochondrial biogenesis in the peripheral blood mononuclear cells (PBMCs) of participants with ovarian cancer were significantly lower than those of the control group. However, the mitochondrial respiratory parameters measured from the PBMCs were similar across all three groups. Furthermore, mitochondrial membrane depolarization and mitochondrial swelling were observed in ovarian tissues of both early-stage and advanced-stage cancer groups. We demonstrated the dynamic nature of mitochondrial ROS production, biogenesis, and respiratory function in response to epithelial ovarian carcinogenesis. The flexibility of mitochondrial functions under diverse conditions may make it a challenging therapeutic target for ovarian cancer.

DOI: https://doi.org/10.1038/s41598-023-51009-z
Curr Biol. 2023 Dec 28. pii: S0960-9822(23)01660-3. [Epub ahead of print]

Mitochondria-derived reactive oxygen species are the likely primary trigger of mitochondrial retrograde signaling in Arabidopsis.

Kasim Khan, Huy Cuong Tran, Berivan Mansuroglu, Pinar Önsell, Stefano Buratti, Markus Schwarzländer, Alex Costa, Allan G Rasmusson, Olivier Van Aken.

  Besides their central function in respiration, plant mitochondria play a crucial role in maintaining cellular homeostasis during stress by providing "retrograde" feedback to the nucleus. Despite the growing understanding of this signaling network, the nature of the signals that initiate mitochondrial retrograde regulation (MRR) in plants remains unknown. Here, we investigated the dynamics and causative relationship of a wide range of mitochondria-related parameters for MRR, using a combination of Arabidopsis fluorescent protein biosensor lines, in vitro assays, and genetic and pharmacological approaches. We show that previously linked physiological parameters, including changes in cytosolic ATP, NADH/NAD+ ratio, cytosolic reactive oxygen species (ROS), pH, free Ca2+, and mitochondrial membrane potential, may often be correlated with-but are not the primary drivers of-MRR induction in plants. However, we demonstrate that the induced production of mitochondrial ROS is the likely primary trigger for MRR induction in Arabidopsis. Furthermore, we demonstrate that mitochondrial ROS-mediated signaling uses the ER-localized ANAC017-pathway to induce MRR response. Finally, our data suggest that mitochondrially generated ROS can induce MRR without substantially leaking into other cellular compartments such as the cytosol or ER lumen, as previously proposed. Overall, our results offer compelling evidence that mitochondrial ROS elevation is the likely trigger of MRR.

Keywords:  Arabidopsis; mitochondria; reactive oxygen species; retrograde signaling

DOI:  https://doi.org/10.1016/j.cub.2023.12.005
EMBO J. 2024 Jan;43(1): 32-60

The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.

Jose M Delgado, Logan Wallace Shepard, Sarah W Lamson, Samantha L Liu, Christopher J Shoemaker.

  Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. This screen revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system and the ubiquitin-proteosome system regulated BNIP3 independently. Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. More broadly, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that tightly regulate endogenous tail-anchored protein localization.

Keywords:  BNIP3; EMC; Mitophagy; Secretory Pathway; TA Protein

DOI:  https://doi.org/10.1038/s44318-023-00006-z
Anal Methods. 2024 Jan 02.

A long-wavelength mitochondria-targeted CO fluorescent probe for living cells and zebrafish imaging.

Xiaodi Rong, Caiyun Liu, Mingzhu Li, Jiafan Shi, Miaohui Yu, Wenlong Sheng, Baocun Zhu, Zhongpeng Wang.

Carbon monoxide (CO) not only causes damage to life and health as an environmental pollutant, but also undertakes many physiological functions in organisms. In particular, developing means that can be used for the determination of CO in organelles will provide insight into the vital role it plays. Studies have shown that mitochondrial respiration is closely related to CO concentrations, so it is critical to develop tools for CO detection in mitochondria. Here, we use a rhodamine derivative that can target mitochondria as fluorophores to construct a mitochondrial-labeled CO fluorescence probe (Rh-CO) with high sensitivity (detection limit: 9.4 nM), excellent water-solubility, and long emission (λem = 630 nm). Prominently, the probe has outstanding mitochondria-targeting capabilities. Moreover, we used transient glucose deprivation (TGD) and heme to stimulate endogenous CO production in living cells and zebrafish, respectively, and the probe exhibited excellent imaging capabilities. All in all, we expect this probe to contribute to a deeper understanding of the role played by CO in mitochondria.

DOI: https://doi.org/10.1039/d3ay01886e
Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00118-6. [Epub ahead of print]75 101838

Mitochondrial density in skeletal and cardiac muscle.

D Pesta.

Kubat et al. provide a review on the role Mitochondrial density in skeletal and cardiac muscle of mitochondrial dysfunction in muscle atrophy. They stress mitochondria's pivotal function, citing a 52 % density in skeletal muscle. However, the reference to Park et al.'s work misinterprets their findings. Park et al. report citrate synthase (CS) activity, indicating mitochondrial density as 222 ± 13 μmol.min-1.mg-1 for cardiac muscle and 115 ± 2 μmol.min-1.mg-1 for skeletal muscle. Thus, the authors should clarify that skeletal muscle density is approximately 52 % of cardiac muscle, not an absolute 52 %. Mitochondrial volume density assessment, predominantly through TEM, establishes cardiomyocytes at 25-30 % and untrained skeletal muscle at 2-6 %, increasing to 11 % in trained athletes. However, this remains modest compared to myofibrils' 75 %-85 % of muscle fiber volume. Although the utility of CS activity is evident, TEM and other novel approaches such as three-dimensional focused ion beam scanning electron microscopy are likely superior for assessing mitochondrial volume density and morphology.

DOI: https://doi.org/10.1016/j.mito.2023.101838
J Cell Physiol. 2024 Jan 01.

Arginine-methylated c-Myc affects mitochondrial mitophagy in mouse acute kidney injury via Slc25a24.

Ying Liu, Naiquan Liu, Ping He, Shiyu Cao, Huabing Li, Dajun Liu.

  The transcription factor methylated c-Myc heterodimerizes with MAX to modulate gene expression, and plays an important role in energy metabolism in kidney injury but the exact mechanism remains unclear. Mitochondrial solute transporter Slc25a24 imports ATP into mitochondria and is central to energy metabolism. Gene Expression Omnibus data analysis reveals Slc25a24 and c-Myc are consistently upregulated in all the acute kidney injury (AKI) cells. Pearson correlation analysis also shows that Slc25a24 and c-Myc are strongly correlated (⍴ > 0.9). Mutant arginine methylated c-Myc (R299A and R346A) reduced its combination with MAX when compared with the wild type of c-Myc. On the other hand, the Slc25a24 levels were also correspondingly reduced, which induced the downregulation of ATP production. The results promoted reactive oxygen species (ROS) production and mitophagy generation. The study revealed that the c-Myc overexpression manifested the most pronounced mitochondrial DNA depletion. Additionally, the varied levels of mitochondrial proteins like TIM23, TOM20, and PINK1 in each group, particularly the elevated levels of PINK1 in AKI model groups and lower levels of TIM23 and TOM20 in the c-Myc overexpression group, suggest potential disruptions in mitochondrial dynamics and homeostasis, indicating enhanced mitophagy or mitochondrial loss. Therefore, arginine-methylated c-Myc affects mouse kidney injury by regulating mitochondrial ATP and ROS, and mitophagy via Slc25a24.

Keywords:  ROS; acute kidney injury; arginine methylation; c-Myc; mitochondrial solute transporter Slc25a24

DOI:  https://doi.org/10.1002/jcp.31160
Biochem J. 2024 Jan 02. pii: BCJ20230450. [Epub ahead of print]

The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography.

Emma Buzzard, Mathew McLaren, Piotr Bragoszewski, Andrea Brancaccio, Holly Ford, Bertram Daum, Patricia Kuwabara, Ian Collinson, Vicki Gold.

  Mitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interface were investigated by comparing C. elegans and S. cerevisiae mitochondrial morphology. We reveal that C. elegans has a larger ATP synthase dimer angle with more lamellar (flatter) cristae when compared to yeast. The underlying cause of this difference was investigated by generating an atomic model of the C. elegans ATP synthase dimer by homology modelling. A comparison of our C. elegans model to an existing S. cerevisiae structure reveals the presence of extensions and rearrangements in C. elegans subunits associated with maintaining the dimer interface. We speculate that increasing dimer angles could provide an advantage for species that inhabit variable-oxygen environments by forming flatter more energetically efficient cristae.

Keywords:  alphafold; atp synthase; cryo-electron microscopy; mitochondria; sub-tomogram averaging

DOI:  https://doi.org/10.1042/BCJ20230450
Sci Rep. 2024 Jan 05. 14(1): 575

Melatonin enhances captopril mediated cardioprotective effects and improves mitochondrial dynamics in male Wistar rats with chronic heart failure.

Sherein F El-Sayed, Amira Mohamed Abdelhamid, Shimaa Gamal ZeinElabdeen, Dalia Ibrahim El-Wafaey, Suzan M M Moursi.

Mitochondrial dysfunction is a recent emerging research scope that proved to be involved in many cardiovascular diseases culminating in chronic heart failure (CHF), which remains one of the primary causes of morbidity and mortality. This study investigated the added cardio-protective effects of exogenous melatonin administration to conventional captopril therapy in isoproterenol (ISO) exposed rats with CHF. Five groups of Wistar rats were recruited; (I): Control group, (II): (ISO group), (III): (ISO + captopril group), (IV): (ISO + melatonin group) and (V): (ISO + melatonin/captopril group). Cardiac function parameters and some oxidant, inflammatory and fibrotic markers were investigated. Moreover; mRNA expression of mitochondrial mitophagy [parkin & PTEN induced kinase 1 (PINK1)], biogenesis [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)], fusion [mitofusin 2 (Mfn2)] and fission [dynamin-related protein 1 (DRP-1)] parameters in rat's myocardium were evaluated. Rats' myocardium was histo-pathologically and immunohistochemically evaluated for Beclin1 and Sirt3 expression. The present study revealed that captopril and melatonin ameliorated cardiac injury, oxidative stress biomarkers, and pro-inflammatory cytokines in ISO-exposed rats. These protective effects could be attributed to mitochondrial dynamic proteins control (i.e. enhanced the mRNA expression of parkin, PINK1, PGC-1α and Mfn2, while reduced DRP-1 mRNA expression). Also, Beclin1 and Sirt3 cardiac immunoreactivity were improved. Combined captopril and melatonin therapy showed a better response than either agent alone. Melatonin enhanced myocardial mitochondrial dynamics and Sirt3 expression in CHF rats and may represent a promising upcoming therapy added to conventional heart failure treatment.

DOI: https://doi.org/10.1038/s41598-023-50730-z