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Mitochondrial Metabolism Alterations in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 59478

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Dr. Graziantonio Lauria

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Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Interests: ketogenic diet; microRNAs signature; catalase; heavy metals metabolic effects; epigenetics; apoptosis; antioxidant effects
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Dr. Rosita Curcio

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Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Interests: bioenergetics; mitochondrial carriers; mutagenesis; drosophila melanogaster; mitochondrial diseases; mitochondrial dysfunction; apoptosis; ROS; antioxidant and anti-inflammatory activity; cancer metabolism; anticancer agents
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Prof. Dr. Vincenza Dolce

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Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Interests: mitochondrial transporters; bioenergetics; mitochondrial diseases; cancers metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are key organelles responsible for cell energy production and are essential for eukaryotic life. They take part in critical metabolic pathways and are fully integrated into intracellular signaling networks, cellular differentiation, and apoptosis. Mitochondrial functions extend beyond cell boundaries and influence the organisms’ physiology by regulating the communication between cells and tissues. Mitochondria are involved in inherited mitochondrial disorders, neurodegenerative diseases, dystrophies, heart failure, cardiac dysfunction, vascular diseases and atherosclerosis, pulmonary and respiratory disorders, renal diseases, metabolic disorders, diabetes, aging, and cancer. Therefore, they are attracting increasing attention with the aim of fully understanding the link between the mitochondrial metabolism and the dysregulation of many cellular processes. This Special Issue will focus on mitochondrial metabolic alterations underlying various pathologies. Original manuscripts and reviews with a particular focus on the physiological role of mitochondria in cell life, as well as their involvement in human diseases assessed in cell lines, animal models, and/or patients, are welcome.

Dr. Graziantonio Lauria
Dr. Rosita Curcio
Prof. Dr. Vincenza Dolce
Guest Editors

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

5 pages, 153 KiB

Open AccessEditorial

Special Issue “Mitochondrial Metabolism Alterations in Health and Disease”

by Graziantonio Lauria and Rosita Curcio

Int. J. Mol. Sci. 2025, 26(10), 4826; https://doi.org/10.3390/ijms26104826 - 18 May 2025

Viewed by 697

Abstract

Mitochondria are central hubs of cellular metabolism and signaling that play key roles in stress response, inflammation, calcium homeostasis, mitochondrial quality control, and cell death, with mitochondrial impairment potentially being the underlying cause of several conditions, including metabolic, neurodegenerative, and cardiovascular diseases [...] [...] Read more.

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

Research

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19 pages, 3301 KiB

Open AccessArticle

Administration of AICAR, an AMPK Activator, Prevents and Reverses Diabetic Polyneuropathy (DPN) by Regulating Mitophagy

by Krish Chandrasekaran, Joungil Choi, Mohammad Salimian, Ahmad F. Hedayat and James W. Russell

Int. J. Mol. Sci. 2025, 26(1), 80; https://doi.org/10.3390/ijms26010080 - 25 Dec 2024

Cited by 2 | Viewed by 2194

Abstract

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in both Type 1 (T1D) and Type 2 (T2D). While there are no specific medications to prevent or treat DPN, certain strategies can help halt its progression. In T1D, maintaining tight glycemic control through insulin therapy can effectively prevent or delay the onset of DPN. However, in T2D, overall glucose control may only have a moderate impact on DPN, although exercise is clearly beneficial. Unfortunately, optimal exercise may not be feasible for many patients with DPN because of neuropathic foot pain and poor balance. Exercise has several favorable effects on health parameters, including body weight, glycemic control, lipid profile, and blood pressure. We investigated the impact of an exercise mimetic, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on DPN. AICAR treatment prevented or reversed experimental DPN in mouse models of both T2D and T1D. AICAR in high-fat diet (HFD-fed) mice increased the phosphorylation of AMPK in DRG neuronal extracts, and the ratio of phosphorylated AMPK to total AMPK increased by 3-fold (HFD vs. HFD+AICAR; p < 0.001). Phospho AMP increased the levels of dynamin-related protein 1 (DRP1, a mitochondrial fission marker), increased phosphorylated autophagy activating kinase 1 (ULK1) at Serine-555, and increased microtubule-associated protein light chain 3-II (LC3-II, a marker for autophagosome assembly) by 2-fold. Mitochondria isolated from DRG neurons of HFD-fed had a decrease in ADP-stimulated state 3 respiration (120 ± 20 nmol O₂/min in HFD vs. 220 ± 20 nmol O₂/min in control diet (CD); p < 0.001. Mitochondria isolated from HFD+AICAR-treated mice had increased state 3 respiration (240 ± 30 nmol O₂/min in HFD+AICAR). However, AICAR’s protection in DPN in T2D mice was also mediated by its effects on insulin sensitivity, glucose metabolism, and lipid metabolism. Drugs that enhance AMPK phosphorylation may be beneficial in the treatment of DPN. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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16 pages, 8236 KiB

Open AccessArticle

Exploiting Glycyrrhiza glabra L. (Licorice) Flavanones: Licoflavanone’s Impact on Breast Cancer Cell Bioenergetics

by Luca Frattaruolo, Graziantonio Lauria, Francesca Aiello, Gabriele Carullo, Rosita Curcio, Marco Fiorillo, Giuseppe Campiani, Vincenza Dolce and Anna Rita Cappello

Int. J. Mol. Sci. 2024, 25(14), 7907; https://doi.org/10.3390/ijms25147907 - 19 Jul 2024

Cited by 6 | Viewed by 1838

Abstract

Research on the energy metabolism of cancer cells is becoming a central element in oncology, and in recent decades, it has allowed us to better understand the mechanisms underlying the onset and chemoresistance of oncological pathologies. Mitochondrial bioenergetic processes, in particular, have proven to be fundamental for the survival of tumor stem cells (CSC), a subpopulation of tumor cells responsible for tumor recurrence, the onset of metastasis, and the failure of conventional anticancer therapies. Over the years, numerous natural products, in particular flavonoids, widely distributed in the plant kingdom, have been shown to interfere with tumor bioenergetics, demonstrating promising antitumor effects. Herein, the anticancer potential of Licoflavanone, a flavanone isolated from the leaves of G. glabra, was explored for the first time in breast cancer cells. The results obtained highlighted a marked antitumor activity that proved to be greater than that mediated by Glabranin or Pinocembrin, flavanones isolated from the same plant matrix. Furthermore, the investigation of Licoflavanone’s effects on breast cancer energy metabolism highlighted the inhibitory activity of this natural product on tumor bioenergetics, a mechanism that could underlie its ability to reduce tumor proliferation, invasiveness, and stemness. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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22 pages, 3385 KiB

Open AccessArticle

Alcohol Impairs Bioenergetics and Differentiation Capacity of Myoblasts from Simian Immunodeficiency Virus-Infected Female Macaques

by Danielle E. Levitt, Brianna L. Bourgeois, Keishla M. Rodríguez-Graciani, Patricia E. Molina and Liz Simon

Int. J. Mol. Sci. 2024, 25(4), 2448; https://doi.org/10.3390/ijms25042448 - 19 Feb 2024

Cited by 6 | Viewed by 1900

Abstract

Alcohol misuse and HIV independently induce myopathy. We previously showed that chronic binge alcohol (CBA) administration, with or without simian immunodeficiency virus (SIV), decreases differentiation capacity of male rhesus macaque myoblasts. We hypothesized that short-term alcohol and CBA/SIV would synergistically decrease differentiation capacity and impair bioenergetic parameters in female macaque myoblasts. Myoblasts from naïve (CBA⁻/SIV⁻), vehicle [VEH]/SIV, and CBA/SIV (N = 4–6/group) groups were proliferated (3 days) and differentiated (5 days) with 0 or 50 mM ethanol (short-term). CBA/SIV decreased differentiation and increased non-mitochondrial oxygen consumption rate (OCR) versus naïve and/or VEH/SIV. Short-term alcohol decreased differentiation; increased maximal and non-mitochondrial OCR, mitochondrial reactive oxygen species (ROS) production, and aldolase activity; and decreased glycolytic measures, ATP production, mitochondrial membrane potential (ΔΨm), and pyruvate kinase activity. Mitochondrial ROS production was closely associated with mitochondrial network volume, and differentiation indices were closely associated with key bioenergetic health and function parameters. Results indicate that short-term alcohol and CBA non-synergistically decrease myoblast differentiation capacity. Short-term alcohol impaired myoblast glycolytic function, driving the bioenergetic deficit. Results suggest potentially differing mechanisms underlying decreased differentiation capacity with short-term alcohol and CBA, highlighting the need to elucidate the impact of different alcohol use patterns on myopathy. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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14 pages, 13748 KiB

Open AccessArticle

Uridine as a Regulator of Functional and Ultrastructural Changes in the Brain of Rats in a Model of 6-OHDA-Induced Parkinson’s Disease

by Nina I. Uspalenko, Alexei A. Mosentsov, Natalia V. Khmil, Lyubov L. Pavlik, Natalia V. Belosludtseva, Natalia V. Khunderyakova, Maria I. Shigaeva, Vasilisa P. Medvedeva, Anton E. Malkov, Valentina F. Kitchigina and Galina D. Mironova

Int. J. Mol. Sci. 2023, 24(18), 14304; https://doi.org/10.3390/ijms241814304 - 19 Sep 2023

Cited by 6 | Viewed by 2854

Abstract

Using a model of Parkinson’s disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca²⁺ retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity. Structural changes occurring in the SN and striatum manifested themselves in the destruction of mitochondria, degeneration of neurons and synapses, and stratification of myelin sheaths in them. Subcutaneous injections of 30 µg/kg uridine for 22 days restored the neurotoxin-induced changes in these parameters to levels close to the control. 5-Hydroxydecanoate (5 mg/kg), a specific mitoK-ATP channel inhibitor, eliminated the beneficial effect of uridine for almost all characteristics tested, indicating the involvement of the mitoK-ATP channel in the protective effect of uridine. The mechanism of the protective effect of uridine and its therapeutic applications for the prevention and treatment of PD are discussed. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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Review

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30 pages, 1902 KiB

Open AccessReview

Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson’s Disease

by Agustina Salis Torres, Ji-Eun Lee, Andrea Caporali, Robert K. Semple, Mathew H. Horrocks and Vicky E. MacRae

Int. J. Mol. Sci. 2024, 25(20), 10973; https://doi.org/10.3390/ijms252010973 - 12 Oct 2024

Cited by 1 | Viewed by 3499

Abstract

Individuals diagnosed with Parkinson’s disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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20 pages, 409 KiB

Open AccessReview

Biomarkers in Thyroid Cancer: Emerging Opportunities from Non-Coding RNAs and Mitochondrial Space

by Patricio Cabané, Claudio Correa, Ignacio Bode, Rodrigo Aguilar and Alvaro A. Elorza

Int. J. Mol. Sci. 2024, 25(12), 6719; https://doi.org/10.3390/ijms25126719 - 18 Jun 2024

Cited by 8 | Viewed by 3112

Abstract

Thyroid cancer diagnosis primarily relies on imaging techniques and cytological analyses. In cases where the diagnosis is uncertain, the quantification of molecular markers has been incorporated after cytological examination. This approach helps physicians to make surgical decisions, estimate cancer aggressiveness, and monitor the response to treatments. Despite the availability of commercial molecular tests, their widespread use has been hindered in our experience due to cost constraints and variability between them. Thus, numerous groups are currently evaluating new molecular markers that ultimately will lead to improved diagnostic certainty, as well as better classification of prognosis and recurrence. In this review, we start reviewing the current preoperative testing methodologies, followed by a comprehensive review of emerging molecular markers. We focus on micro RNAs, long non-coding RNAs, and mitochondrial (mt) signatures, including mtDNA genes and circulating cell-free mtDNA. We envision that a robust set of molecular markers will complement the national and international clinical guides for proper assessment of the disease. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

18 pages, 1992 KiB

Open AccessReview

Mitochondrial One-Carbon Metabolism and Alzheimer’s Disease

by Yizhou Yu and L. Miguel Martins

Int. J. Mol. Sci. 2024, 25(12), 6302; https://doi.org/10.3390/ijms25126302 - 7 Jun 2024

Cited by 5 | Viewed by 3103

Abstract

Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer’s disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer’s disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer’s disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer’s disease pathology. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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24 pages, 1593 KiB

Open AccessReview

Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials

by Dong-Oh Moon

Int. J. Mol. Sci. 2024, 25(4), 2129; https://doi.org/10.3390/ijms25042129 - 9 Feb 2024

Cited by 5 | Viewed by 2901

Abstract

ATP-sensitive potassium (KATP) channels are found in plasma membranes and mitochondria. These channels are a type of ion channel that is regulated by the intracellular concentration of adenosine triphosphate (ATP) and other nucleotides. In cell membranes, they play a crucial role in linking metabolic activity to electrical activity, especially in tissues like the heart and pancreas. In mitochondria, KATP channels are involved in protecting cells against ischemic damage and regulating mitochondrial function. This review delves into the role of KATP channels in cancer biology, underscoring their critical function. Notably responsive to changes in cellular metabolism, KATP channels link metabolic states to electrical activity, a feature that becomes particularly significant in cancer cells. These cells, characterized by uncontrolled growth, necessitate unique metabolic and signaling pathways, differing fundamentally from normal cells. Our review explores the intricate roles of KATP channels in influencing the metabolic and ionic balance within cancerous cells, detailing their structural and operational mechanisms. We highlight the channels’ impact on cancer cell survival, proliferation, and the potential of KATP channels as therapeutic targets in oncology. This includes the challenges in targeting these channels due to their widespread presence in various tissues and the need for personalized treatment strategies. By integrating molecular biology, physiology, and pharmacology perspectives, the review aims to enhance the understanding of cancer as a complex metabolic disease and to open new research and treatment avenues by focusing on KATP channels. This comprehensive approach provides valuable insights into the potential of KATP channels in developing innovative cancer treatments. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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17 pages, 2552 KiB

Open AccessReview

Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview

by David Mantle, Iain Parry Hargreaves, Joan Carles Domingo and Jesus Castro-Marrero

Int. J. Mol. Sci. 2024, 25(1), 574; https://doi.org/10.3390/ijms25010574 - 1 Jan 2024

Cited by 31 | Viewed by 34075

Abstract

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown causes characterised by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS); fibromyalgia (FM); and more recently post-COVID-19 condition (long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. The accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and long COVID. To address this issue, this article aims to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, it aims to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)

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