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17 pages, 7783 KiB

Open AccessArticle

Differential Mitochondrial, Oxidative Stress and Inflammatory Responses to SARS-CoV-2 Spike Protein Receptor Binding Domain in Human Lung Microvascular, Coronary Artery Endothelial and Bronchial Epithelial Cells

by Gabrielė Kulkovienė, Deimantė Narauskaitė, Agilė Tunaitytė, Augusta Volkevičiūtė, Zbigniev Balion, Olena Kutakh, Dovydas Gečys, Milda Kairytė, Martyna Uldukytė, Edgaras Stankevičius and Aistė Jekabsone

Int. J. Mol. Sci. 2024, 25(6), 3188; https://doi.org/10.3390/ijms25063188 - 10 Mar 2024

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Abstract

Recent evidence indicates that the SARS-CoV-2 spike protein affects mitochondria with a cell type-dependent outcome. We elucidate the effect of the SARS-CoV-2 receptor binding domain (RBD) on the mitochondrial network and cristae morphology, oxygen consumption, mitoROS production, and inflammatory cytokine expression in cultured [...] Read more.

Recent evidence indicates that the SARS-CoV-2 spike protein affects mitochondria with a cell type-dependent outcome. We elucidate the effect of the SARS-CoV-2 receptor binding domain (RBD) on the mitochondrial network and cristae morphology, oxygen consumption, mitoROS production, and inflammatory cytokine expression in cultured human lung microvascular (HLMVECs), coronary artery endothelial (HCAECs), and bronchial epithelial cells (HBECs). Live Mito Orange staining, STED microscopy, and Fiji MiNa analysis were used for mitochondrial cristae and network morphometry; an Agilent XFp analyser for mitochondrial/glycolytic activity; MitoSOX fluorescence for mitochondrial ROS; and qRT-PCR plus Luminex for cytokines. HLMVEC exposure to SARS-CoV-2 RBD resulted in the fragmentation of the mitochondrial network, mitochondrial swelling, increased cristae area, reduced cristae density, and suppressed mitochondrial oxygen consumption and glycolysis. No significant mitochondrial morphology or oxygen consumption changes were observed in HCAECs and HBECs. SARS-CoV-2 RBD induced mitoROS-mediated expression of cytokines GM-CSF and IL-1β in all three investigated cell types, along with IL-8 expression in both endothelial cell types. The findings suggest mitochondrial ROS control SARS-CoV-2 RBD-induced inflammation in HLMVECs, HCAECs, and HBECs, with the mitochondria of HLMVECs being more sensitive to SARS-CoV-2 RBD. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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17 pages, 5464 KiB

Open AccessArticle

Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes

by Eirini Taouktsi, Eleni Kyriakou, Evangelia Voulgaraki, Dimitris Verganelakis, Stefania Krokou, Stamatis Rigas, Gerassimos E. Voutsinas and Popi Syntichaki

Int. J. Mol. Sci. 2023, 24(24), 17209; https://doi.org/10.3390/ijms242417209 - 7 Dec 2023

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Abstract

p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In C. elegans, mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPK^mt), but its functional role still remains elusive. Here, we demonstrate [...] Read more.

p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In C. elegans, mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPK^mt), but its functional role still remains elusive. Here, we demonstrate the induction of MAPK^mt in worms deficient in the lonp-1 gene, which encodes the worm ortholog of mammalian mitochondrial LonP1. This induction is subjected to negative regulation by the ATFS-1 transcription factor through the CREB-binding protein (CBP) ortholog CBP-3, indicating an interplay between both activated MAPK^mt and mitochondrial Unfolded Protein Response (UPR^mt) surveillance pathways. Our results also reveal a genetic interaction in lonp-1 mutants between PMK-3 kinase and the ZIP-2 transcription factor. ZIP-2 has an established role in innate immunity but can also modulate the lifespan by maintaining mitochondrial homeostasis during ageing. We show that in lonp-1 animals, ZIP-2 is activated in a PMK-3-dependent manner but does not confer increased survival to pathogenic bacteria. However, deletion of zip-2 or pmk-3 shortens the lifespan of lonp-1 mutants, suggesting a possible crosstalk under conditions of mitochondrial perturbation that influences the ageing process. Furthermore, loss of pmk-3 specifically diminished the extreme heat tolerance of lonp-1 worms, highlighting the crucial role of PMK-3 in the heat shock response upon mitochondrial LONP-1 inactivation. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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15 pages, 1772 KiB

Open AccessArticle

Mitochondrial Dysfunction in Skeletal Muscle of Rotenone-Induced Rat Model of Parkinson’s Disease: SC-Nanophytosomes as Therapeutic Approach

by Daniela Mendes, Francisco Peixoto, Maria Manuel Oliveira, Paula Branquinho Andrade and Romeu António Videira

Int. J. Mol. Sci. 2023, 24(23), 16787; https://doi.org/10.3390/ijms242316787 - 27 Nov 2023

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Abstract

The development of new therapeutic options for Parkinson’s disease (PD) requires formulations able to mitigate both brain degeneration and motor dysfunctions. SC-Nanophytosomes, an oral mitochondria-targeted formulation developed with Codium tomentosum membrane polar lipids and elderberry anthocyanin-enriched extract, promote significant brain benefits on [...] Read more.

The development of new therapeutic options for Parkinson’s disease (PD) requires formulations able to mitigate both brain degeneration and motor dysfunctions. SC-Nanophytosomes, an oral mitochondria-targeted formulation developed with Codium tomentosum membrane polar lipids and elderberry anthocyanin-enriched extract, promote significant brain benefits on a rotenone-induced rat model of PD. In the present work, the effects of SC-Nanophytosome treatment on the skeletal muscle tissues are disclosed. It is unveiled that the rotenone-induced PD rat model exhibits motor disabilities and skeletal muscle tissues with deficient activity of mitochondrial complexes I and II along with small changes in antioxidant enzyme activity and skeletal muscle lipidome. SC-Nanophytosome treatment mitigates the impairment of complexes I and II activity, improving the mitochondrial respiratory chain performance at levels that surpass the control. Therefore, SC-Nanophytosome competence to overcome the PD-related motor disabilities should be also associated with its positive outcomes on skeletal muscle mitochondria. Providing a cellular environment with more reduced redox potential, SC-Nanophytosome treatment improves the skeletal muscle tissue’s ability to deal with oxidative stress stimuli. The PD-related small changes on skeletal muscle lipidome were also counteracted by SC-Nanophytosome treatment. Thus, the present results reinforces the concept of SC-Nanophytosomes as a mitochondria-targeted therapy to address the neurodegeneration challenge. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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14 pages, 2018 KiB

Open AccessArticle

The Natural Alkaloid Palmatine Selectively Induces Mitophagy and Restores Mitochondrial Function in an Alzheimer’s Disease Mouse Model

by Da-Ye Lee, Kang-Min Lee, Jee-Hyun Um, Young-Yeon Kim, Dong-Hyun Kim and Jeanho Yun

Int. J. Mol. Sci. 2023, 24(22), 16542; https://doi.org/10.3390/ijms242216542 - 20 Nov 2023

Cited by 2 | Viewed by 1221

Abstract

Palmatine, a natural alkaloid found in various plants, has been reported to have diverse pharmacological and biological effects, including anti-inflammatory, antioxidant, and cardiovascular effects. However, the role of palmatine in mitophagy, a fundamental process crucial for maintaining mitochondrial function, remains elusive. In this [...] Read more.

Palmatine, a natural alkaloid found in various plants, has been reported to have diverse pharmacological and biological effects, including anti-inflammatory, antioxidant, and cardiovascular effects. However, the role of palmatine in mitophagy, a fundamental process crucial for maintaining mitochondrial function, remains elusive. In this study, we found that palmatine efficiently induces mitophagy in various human cell lines. Palmatine specifically induces mitophagy and subsequently stimulates mitochondrial biogenesis. Palmatine did not interfere with mitochondrial function, similar to CCCP, suggesting that palmatine is not toxic to mitochondria. Importantly, palmatine treatment alleviated mitochondrial dysfunction in PINK1-knockout MEFs. Moreover, the administration of palmatine resulted in significant improvements in cognitive function and restored mitochondrial function in an Alzheimer’s disease mouse model. This study identifies palmatine as a novel inducer of selective mitophagy. Our results suggest that palmatine-mediated mitophagy induction could be a potential strategy for Alzheimer’s disease treatment and that natural alkaloids are potential sources of mitophagy inducers. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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Review

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16 pages, 7752 KiB

Open AccessReview

The Structure of the Cardiac Mitochondria Respirasome Is Adapted for the β-Oxidation of Fatty Acids

by Alexander V. Panov

Int. J. Mol. Sci. 2024, 25(4), 2410; https://doi.org/10.3390/ijms25042410 - 18 Feb 2024

Viewed by 1231

Abstract

It is well known that in the heart and kidney mitochondria, more than 95% of ATP production is supported by the β-oxidation of long-chain fatty acids. However, the β-oxidation of fatty acids by mitochondria has been studied much less than the substrates formed [...] Read more.

It is well known that in the heart and kidney mitochondria, more than 95% of ATP production is supported by the β-oxidation of long-chain fatty acids. However, the β-oxidation of fatty acids by mitochondria has been studied much less than the substrates formed during the catabolism of carbohydrates and amino acids. In the last few decades, several discoveries have been made that are directly related to fatty acid oxidation. In this review, we made an attempt to re-evaluate the β-oxidation of long-chain fatty acids from the perspectives of new discoveries. The single set of electron transporters of the cardiac mitochondrial respiratory chain is organized into three supercomplexes. Two of them contain complex I, a dimer of complex III, and two dimers of complex IV. The third, smaller supercomplex contains a dimer of complex III and two dimers of complex IV. We also considered other important discoveries. First, the enzymes of the β-oxidation of fatty acids are physically associated with the respirasome. Second, the β-oxidation of fatty acids creates the highest level of QH₂ and reverses the flow of electrons from QH₂ through complex II, reducing fumarate to succinate. Third, β-oxidation is greatly stimulated in the presence of succinate. We argue that the respirasome is uniquely adapted for the β-oxidation of fatty acids. The acyl-CoA dehydrogenase complex reduces the membrane’s pool of ubiquinone to QH₂, which is instantly oxidized by the smaller supercomplex, generating a high energization of mitochondria and reversing the electron flow through complex II, which reverses the electron flow through complex I, increasing the NADH/NAD⁺ ratio in the matrix. The mitochondrial nicotinamide nucleotide transhydrogenase catalyzes a hydride (H^-, a proton plus two electrons) transfer across the inner mitochondrial membrane, reducing the cytosolic pool of NADP(H), thus providing the heart with ATP for muscle contraction and energy and reducing equivalents for the housekeeping processes. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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31 pages, 2296 KiB

Open AccessReview

Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression

by Rajakrishnan Veluthakal, Diana Esparza, Joseph M. Hoolachan, Rekha Balakrishnan, Miwon Ahn, Eunjin Oh, Chathurani S. Jayasena and Debbie C. Thurmond

Int. J. Mol. Sci. 2024, 25(3), 1504; https://doi.org/10.3390/ijms25031504 - 25 Jan 2024

Cited by 1 | Viewed by 1753

Abstract

Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the [...] Read more.

Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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14 pages, 1048 KiB

Open AccessReview

The Research Progress of Mitochondrial Transplantation in the Treatment of Mitochondrial Defective Diseases

by Cuilan Hu, Zheng Shi, Xiongxiong Liu and Chao Sun

Int. J. Mol. Sci. 2024, 25(2), 1175; https://doi.org/10.3390/ijms25021175 - 18 Jan 2024

Cited by 1 | Viewed by 1353

Abstract

Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria [...] Read more.

Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria from healthy tissues into diseased tissues with damaged mitochondria to rescue the injured cells. In this review, the different mitochondrial transplantation techniques and their clinical applications have been discussed. In addition, the challenges and future directions pertaining to mitochondrial transplantation and its potential in the treatment of diseases with defective mitochondria have been summarized. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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24 pages, 1419 KiB

Open AccessReview

From Beach to the Bedside: Harnessing Mitochondrial Function in Human Diseases Using New Marine-Derived Strategies

by Serena Mirra and Gemma Marfany

Int. J. Mol. Sci. 2024, 25(2), 834; https://doi.org/10.3390/ijms25020834 - 9 Jan 2024

Cited by 1 | Viewed by 1317

Abstract

Mitochondria are double-membrane organelles within eukaryotic cells that act as cellular power houses owing to their ability to efficiently generate the ATP required to sustain normal cell function. Also, they represent a “hub” for the regulation of a plethora of processes, including cellular [...] Read more.

Mitochondria are double-membrane organelles within eukaryotic cells that act as cellular power houses owing to their ability to efficiently generate the ATP required to sustain normal cell function. Also, they represent a “hub” for the regulation of a plethora of processes, including cellular homeostasis, metabolism, the defense against oxidative stress, and cell death. Mitochondrial dysfunctions are associated with a wide range of human diseases with complex pathologies, including metabolic diseases, neurodegenerative disorders, and cancer. Therefore, regulating dysfunctional mitochondria represents a pivotal therapeutic opportunity in biomedicine. Marine ecosystems are biologically very diversified and harbor a broad range of organisms, providing both novel bioactive substances and molecules with meaningful biomedical and pharmacological applications. Recently, many mitochondria-targeting marine-derived molecules have been described to regulate mitochondrial biology, thus exerting therapeutic effects by inhibiting mitochondrial abnormalities, both in vitro and in vivo, through different mechanisms of action. Here, we review different strategies that are derived from marine organisms which modulate specific mitochondrial processes or mitochondrial molecular pathways and ultimately aim to find key molecules to treat a wide range of human diseases characterized by impaired mitochondrial function. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease 2.0)

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