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Cells
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Mitochondria at the Crossroad of Health and Disease—Second Edition
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Mitochondria at the Crossroad of Health and Disease—Second Edition

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (20 January 2026) | Viewed by 3667

Special Issue Editor

Prof. Dr. Nickolay Brustovetsky

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Interests: mitochondria; bioenergetics; neuron; calcium; neurodegeneration; cell death; Huntington's disease; Alzheimer's disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are the key organelles in the aerobic cell. They have multiple functions, which significantly impact cell life and death. Mitochondria are the main consumers of oxygen and producers of ATP, supporting energy-demanding processes in the cell. Mitochondrial oxidative metabolism unavoidably results in the generation of reactive oxygen species (ROS), which may significantly contribute to oxidative stress under pathological conditions. Mitochondria play a very important role in calcium signaling by taking up significant amounts of calcium during excessive calcium influx in the cell or substantial calcium release from endoplasmic reticulum. The calcium overload of mitochondria may induce a mitochondrial permeability transition pore that causes mitochondrial depolarization, leading to inhibition of ATP production in mitochondria, and mitochondrial swelling, resulting in the rupture of the mitochondrial outer membrane and release of cytochrome c and other apoptogenic proteins. Mitochondrial health is maintained by selective elimination of damaged organelles in the process of mitophagy. Mitochondrial dynamics, the ability to move along microtubules and undergo fragmentation (fission) and elongation (fusion), significantly contributes to mitochondrial quality control and elimination of damaged organelles. These processes are well-coordinated in healthy cells but can go awry in different pathologies, in aging, and in age-related diseases. There is a great deal of information about mitochondrial biology, but there are still a lot of unanswered questions regarding the functioning of healthy mitochondria and the mechanisms of mitochondrial dysfunction in aging and age-related pathologies. Consequently, this Special Issue is devoted to new developments in mitochondrial biology and is aimed at elucidating the mechanisms of mitochondrial dysfunction under various pathologies, in healthy aging and age-related diseases. We invite authors to contribute original research papers as well as review articles. We encourage authors to share their exciting recent findings addressing new developments in mitochondrial biology and clarifying the mechanisms of mitochondrial dysfunction under various conditions.

Prof. Dr. Nickolay Brustovetsky
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mitochondria
  • oxidative phosphorylation
  • mitochondrial ion transport
  • permeability transition pore
  • mitochondrial ROS generation
  • mitochondrial quality control
  • mitochondrial traffic
  • mitochondrial morphology
  • mitochondrial dynamics
  • mitophagy

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Related Special Issue

Published Papers (4 papers)

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Research

16 pages, 1760 KB  
Article
Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease
by Beatrisa Rimskaya, Ekaterina Kropocheva, Elza Shchukina, Egor Ulashchik, Daria Gelfenbein, Lidiya Lisitskaya, Vadim Shmanai, Svetlana Smirnikhina, Andrey Kulbachinskiy and Ilya Mazunin
Cells 2026, 15(2), 127; https://doi.org/10.3390/cells15020127 - 10 Jan 2026
Viewed by 230
Abstract
Manipulating the mitochondrial genome remains a significant challenge in genetic engineering, primarily due to the mitochondrial double-membrane structure. While recent advances have expanded the genetic toolkit for nuclear and cytoplasmic targets, precise editing of mitochondrial DNA (mtDNA) has remained elusive. Here we report [...] Read more.
Manipulating the mitochondrial genome remains a significant challenge in genetic engineering, primarily due to the mitochondrial double-membrane structure. While recent advances have expanded the genetic toolkit for nuclear and cytoplasmic targets, precise editing of mitochondrial DNA (mtDNA) has remained elusive. Here we report the first successful mitochondrial import of a catalytically active RNA-guided prokaryotic Argonaute protein from the mesophilic bacterium Alteromonas macleodii (AmAgo). By guiding AmAgo to the single-stranded D- or R-loop region of mtDNA using synthetic RNA guides, we observed a nearly threefold reduction in mtDNA copy number in human cell lines. This proof of concept study demonstrates that a bacterial Argonaute can remain active within the mitochondrial environment and influence mtDNA levels. These findings establish a foundational framework for further development of programmable systems for mitochondrial genome manipulation. Full article
(This article belongs to the Special Issue Mitochondria at the Crossroad of Health and Disease—Second Edition)
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19 pages, 4128 KB  
Article
Dissecting the Biological Functions of Various Isoforms of Ferredoxin Reductase for Cell Survival and DNA Damage Response
by Ken-ichi Nakajima, Shakur Mohibi, Kyle Hong, Xinbin Chen and Jin Zhang
Cells 2026, 15(1), 62; https://doi.org/10.3390/cells15010062 - 29 Dec 2025
Viewed by 318
Abstract
The ferredoxin reductase (FDXR) gene is expressed as seven isoforms: 1–6 by alternative splicing and 7 by an alternative promoter according to the Entrez Gene Database. Previous studies showed that FDXR, primarily the mitochondrial isoform 1, plays a role in biosynthesis of [...] Read more.
The ferredoxin reductase (FDXR) gene is expressed as seven isoforms: 1–6 by alternative splicing and 7 by an alternative promoter according to the Entrez Gene Database. Previous studies showed that FDXR, primarily the mitochondrial isoform 1, plays a role in biosynthesis of sterols, heme, and iron–sulfur clusters. However, the biological functions of FDXR isoforms 3–7 have not been characterized. Here, we first examined the expression profile of various FDXR isoforms. We found that isoform 1 is the most abundant one, accounting for ~70% of total FDXR, whereas isoforms 4 and 7 account for ~10% and ~7%, respectively. We found that isoforms 1 and 4 are mainly localized in the mitochondria, whereas isoform 7, which lacks a mitochondria localization signal (MLS), is expressed in the cytosol. We also found that like the promoter 1 for isoforms 1-6, the P2 promoter for isoform 7 can be induced by DNA damage in a p53-dependent manner. To determine isoform-specific activity, we generated multiple MCF7 cell lines in which one or more FDXR isoforms are knocked out. While total FDXR-KO MCF7 cells are non-viable, cells deficient in isoforms 1–6, isoform 4, or isoform 7 remain viable but are defective in cell proliferation, DNA damage response, and repair. These data suggest that each FDXR isoform contributes to cell survival and that isoform 7 has extra-mitochondrial activity that may be sufficient for cell survival. Full article
(This article belongs to the Special Issue Mitochondria at the Crossroad of Health and Disease—Second Edition)
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15 pages, 1664 KB  
Article
Mitochondrial Protection by Astaxanthin Reduces Toxicity Caused by H2O2 and Doxorubicin in Human Cardiomyocytes
by Yulia Baburina, Aleksey Lomovsky, Yana Lomovskaya, Roman Sotnikov, Linda Sotnikova and Olga Krestinina
Cells 2025, 14(22), 1772; https://doi.org/10.3390/cells14221772 - 12 Nov 2025
Viewed by 806
Abstract
Astaxanthin (AST) is a xanthophyll carotenoid known for its cardioprotective effects. In this study, we investigated the impact of AST on the survival of AC16 human cardiomyocytes under cardiotoxic conditions induced by hydrogen peroxide (H2O2) and doxorubicin (DOX). We [...] Read more.
Astaxanthin (AST) is a xanthophyll carotenoid known for its cardioprotective effects. In this study, we investigated the impact of AST on the survival of AC16 human cardiomyocytes under cardiotoxic conditions induced by hydrogen peroxide (H2O2) and doxorubicin (DOX). We assessed a series of parameters associated with cell death signaling, including: changes in cytosolic Ca2+ levels and reactive oxygen species (ROS) production; alterations in mitochondrial function (membrane potential ΔΨm and the content of key subunits of complexes I and II); and the levels of key apoptotic and ER stress markers. Our findings show that AST prevented the cytotoxic effects of both H2O2 and DOX. In the presence of AST, the number of viable cells increased, while Ca2+ levels, ROS production, and ΔΨm remained comparable to those in the control group. Furthermore, AST prevented the H2O2-induced decrease in the levels of the main subunits of respiratory chain complexes I and II. AST prevented the H2O2-induced increase in the levels of apoptotic caspases-8 and -3. It also protected against ER stress by counteracting the H2O2-mediated upregulation of BIP, CHOP, and ERO1α proteins. These results lead us to conclude that AST exerts a protective effect by inhibiting mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Mitochondria at the Crossroad of Health and Disease—Second Edition)
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22 pages, 4136 KB  
Article
Collapsin Response Mediator Protein 2 (CRMP2) Modulates Mitochondrial Oxidative Metabolism in Knock-In AD Mouse Model
by Tatiana Brustovetsky, Rajesh Khanna and Nickolay Brustovetsky
Cells 2025, 14(9), 647; https://doi.org/10.3390/cells14090647 - 29 Apr 2025
Viewed by 1581
Abstract
We explored how the phosphorylation state of collapsin response mediator protein 2 (CRMP2) influences mitochondrial functions in cultured cortical neurons and cortical synaptic mitochondria isolated from APP-SAA KI mice, a knock-in APP mouse model of Alzheimer’s disease (AD). CRMP2 phosphorylation was increased at [...] Read more.
We explored how the phosphorylation state of collapsin response mediator protein 2 (CRMP2) influences mitochondrial functions in cultured cortical neurons and cortical synaptic mitochondria isolated from APP-SAA KI mice, a knock-in APP mouse model of Alzheimer’s disease (AD). CRMP2 phosphorylation was increased at Thr 509/514 and Ser 522 in brain cortical lysates and cultured neurons from AD mice. The basal and maximal respiration of AD neurons were decreased. Mitochondria were hyperpolarized and superoxide anion production was increased in neurons from AD mice. In isolated synaptic AD mitochondria, ADP-stimulated and DNP-stimulated respiration were decreased, whereas ADP-induced mitochondrial depolarization was reduced and prolonged. We found that CRMP2 binds to the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. The increased CRMP2 phosphorylation in AD mice correlated with CRMP2 dissociation from the ANT and decreased ANT activity in AD mitochondria. On the other hand, recombinant CRMP2 (rCRMP2), added to the ANT-reconstituted proteoliposomes, increased ANT activity. A small molecule (S)-lacosamide ((S)-LCM), which binds to CRMP2 and suppresses CRMP2 phosphorylation by Cdk5 and GSK-3β, prevented CRMP2 hyperphosphorylation, rescued CRMP2 binding to the ANT, improved ANT activity, and restored the mitochondrial membrane potential and respiratory responses to ADP and 2,4-dinitrophenol. Thus, our study highlights an important role for CRMP2 in regulating the mitochondrial oxidative metabolism in AD by modulating the ANT activity in a phosphorylation-dependent manner. Full article
(This article belongs to the Special Issue Mitochondria at the Crossroad of Health and Disease—Second Edition)
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