Life | Special Issue : Mitochondria: From Physiology to Pathology

Editorial

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4 pages, 192 KiB

Open AccessEditorial

Mitochondria: From Physiology to Pathology

by Francesco Bruni

Life 2021, 11(9), 991; https://doi.org/10.3390/life11090991 - 21 Sep 2021

Cited by 8 | Viewed by 1825

Abstract

Over the past decade, the role of mitochondria has extended beyond those tasks for which these organelles are historically known [...] Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

Research

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20 pages, 1094 KiB

Open AccessArticle

Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients

by Matthew J. Young, Ravi Sachidanandam, Dale B. Hales, Laurent Brard, Kathy Robinson, Md. Mostafijur Rahman, Pabitra Khadka, Kathleen Groesch and Carolyn K. J. Young

Life 2022, 12(4), 562; https://doi.org/10.3390/life12040562 - 09 Apr 2022

Cited by 3 | Viewed by 3384

Abstract

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and [...] Read more.

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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18 pages, 2502 KiB

Open AccessArticle

Subcellular Localization of Fad1p in Saccharomyces cerevisiae: A Choice at Post-Transcriptional Level?

by Francesco Bruni, Teresa Anna Giancaspero, Mislav Oreb, Maria Tolomeo, Piero Leone, Eckhard Boles, Marina Roberti, Michele Caselle and Maria Barile

Life 2021, 11(9), 967; https://doi.org/10.3390/life11090967 - 14 Sep 2021

Cited by 2 | Viewed by 2038

Abstract

FAD synthase is the last enzyme in the pathway that converts riboflavin into FAD. In Saccharomyces cerevisiae, the gene encoding for FAD synthase is FAD1, from which a sole protein product (Fad1p) is expected to be generated. In this work, we [...] Read more.

FAD synthase is the last enzyme in the pathway that converts riboflavin into FAD. In Saccharomyces cerevisiae, the gene encoding for FAD synthase is FAD1, from which a sole protein product (Fad1p) is expected to be generated. In this work, we showed that a natural Fad1p exists in yeast mitochondria and that, in its recombinant form, the protein is able, per se, to both enter mitochondria and to be destined to cytosol. Thus, we propose that FAD1 generates two echoforms—that is, two identical proteins addressed to different subcellular compartments. To shed light on the mechanism underlying the subcellular destination of Fad1p, the 3′ region of FAD1 mRNA was analyzed by 3′RACE experiments, which revealed the existence of (at least) two FAD1 transcripts with different 3′UTRs, the short one being 128 bp and the long one being 759 bp. Bioinformatic analysis on these 3′UTRs allowed us to predict the existence of a cis-acting mitochondrial localization motif, present in both the transcripts and, presumably, involved in protein targeting based on the 3′UTR context. Here, we propose that the long FAD1 transcript might be responsible for the generation of mitochondrial Fad1p echoform. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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17 pages, 2340 KiB

Open AccessArticle

Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

by Francesco Capriglia, Francesca Rizzo, Giuseppe Petrosillo, Veronica Morea, Giulia d’Amati, Palmiro Cantatore, Marina Roberti, Paola Loguercio Polosa and Francesco Bruni

Life 2021, 11(7), 674; https://doi.org/10.3390/life11070674 - 10 Jul 2021

Cited by 8 | Viewed by 2509

Abstract

The m.3243A>G mutation within the mitochondrial mt-tRNALeu^(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, [...] Read more.

The m.3243A>G mutation within the mitochondrial mt-tRNALeu^(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification. In transmitochondrial cybrids, overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) has proven effective in rescuing the phenotype associated with m.3243A>G substitution. The rescuing activity resides in the carboxy-terminal domain (Cterm) of the enzyme; however, the precise molecular mechanisms underlying this process have not been fully elucidated. To deepen our knowledge on the rescuing mechanisms, we demonstrated the interactions of the Cterm with mutated mt-tRNALeu^(UUR) and its precursor in MELAS cybrids. Further, the effect of Cterm expression on mitochondrial functions was evaluated. We found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu^(UUR) steady-state levels and aminoacylation. Despite the complete recovery of cell viability and the increase in mitochondrial translation, Cterm-overexpressing cybrids were not able to recover bioenergetic competence. These data suggest that, in our MELAS cell model, the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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17 pages, 2557 KiB

Open AccessArticle

Dependence of Leydig Cell’s Mitochondrial Physiology on Luteinizing Hormone Signaling

by Marija L. J. Medar, Dijana Z. Marinkovic, Zvezdana Kojic, Alisa P. Becin, Isidora M. Starovlah, Tamara Kravic-Stevovic, Silvana A. Andric and Tatjana S. Kostic

Life 2021, 11(1), 19; https://doi.org/10.3390/life11010019 - 31 Dec 2020

Cited by 14 | Viewed by 3095

Abstract

Knowledge about the relationship between steroidogenesis and the regulation of the mitochondrial bioenergetics and dynamics, in steroidogenic cells, is not completely elucidated. Here we employed in vivo and ex vivo experimental models to analyze mitochondrial physiology in Leydig cells depending on the different [...] Read more.

Knowledge about the relationship between steroidogenesis and the regulation of the mitochondrial bioenergetics and dynamics, in steroidogenic cells, is not completely elucidated. Here we employed in vivo and ex vivo experimental models to analyze mitochondrial physiology in Leydig cells depending on the different LH-cAMP environments. Activation of LH-receptor in rat Leydig cells ex and in vivo triggered cAMP, increased oxygen consumption, mitoenergetic and steroidogenic activities. Increased mitoenergetic activity i.e., ATP production is achieved through augmented glycolytic ATP production and a small part of oxidative phosphorylation (OXPHOS). Transcription of major genes responsible for mitochondrial dynamics was upregulated for Ppargc1a (regulator of mitogenesis and function) and downregulated for Drp1 (main fission marker), Prkn, Pink1 and Tfeb (mitophagy markers). Leydig cells from gonadotropin-treated rats show increased mitogenesis confirmed by increased mitochondrial mass, increased mtDNA, more frequent mitochondria observed by a transmission electron microscope and increased expression of subunits of respiratory proteins Cytc/CYTC and COX4. Opposite, Leydig cells from hypogonadotropic-hypogonadal rats characterized by low LH-cAMP, testosterone, and ATP production, reduced markers of mitogenesis and mitofusion (Mfn1/2, Opa1) associated with reduced mtDNA content. Altogether results underline LH-cAMP signaling as an important regulator of mitochondrial physiology arranging mitochondrial dynamics, bioenergetic and steroidogenic function in Leydig cells. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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9 pages, 604 KiB

Open AccessArticle

Impact of Mitochondrial DNA Mutations on Carotid Intima-Media Thickness in the Novosibirsk Region

by Tatiana V. Kirichenko, Anastasia I. Ryzhkova, Vasily V. Sinyov, Marina D. Sazonova, Varvara A. Orekhova, Vasily P. Karagodin, Elena V. Gerasimova, Mikhail I. Voevoda, Alexander N. Orekhov, Yulia I. Ragino, Igor A. Sobenin and Margarita A. Sazonova

Life 2020, 10(9), 160; https://doi.org/10.3390/life10090160 - 22 Aug 2020

Cited by 4 | Viewed by 2244

Abstract

The search for markers of predisposition to atherosclerosis development is very important for early identification of individuals with a high risk of cardiovascular disease. The aim of the present study was to investigate the association of mitochondrial DNA mutations with carotid intima-media thickness [...] Read more.

The search for markers of predisposition to atherosclerosis development is very important for early identification of individuals with a high risk of cardiovascular disease. The aim of the present study was to investigate the association of mitochondrial DNA mutations with carotid intima-media thickness and to determine the impact of mitochondrial heteroplasmy measurements in the prognosis of atherosclerosis development. This cross-sectional, population-based study was conducted in 468 subjects from the Novosibirsk region. It was shown that the mean (carotid intima-media thickness) cIMT correlated with the following mtDNA mutations: m.15059G>A (r = 0.159, p = 0.001), m.12315G>A (r = 0.119; p = 0.011), m.5178C>A (r = 0.114, p = 0.014), and m.3256C>T (r = 0.130, p = 0.011); a negative correlation with mtDNA mutations m.14846G>A (r = −0.111, p = 0.042) and m.13513G>A (r = −0.133, p = 0.004) was observed. In the linear regression analysis, the addition of the set of mtDNA mutations to the conventional cardiovascular risk factors increased the ability to predict the cIMT variability from 17 to 27%. Multi-step linear regression analysis revealed the most important predictors of mean cIMT variability: age, systolic blood pressure, blood levels of total cholesterol, LDL and triglycerides, as well as the mtDNA mutations m.13513G>A, m.15059G>A, m.12315G>A, and m.3256C>T. Thus, a high predictive value of mtDNA mutations for cIMT variability was demonstrated. The association of mutation m.13513G>A and m.14846G>A with a low value of cIMT, demonstrated in several studies, represents a potential for the development of anti-atherosclerotic gene therapy. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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Review

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15 pages, 989 KiB

Open AccessReview

PINK1: A Bridge between Mitochondria and Parkinson’s Disease

by Filipa Barroso Gonçalves and Vanessa Alexandra Morais

Life 2021, 11(5), 371; https://doi.org/10.3390/life11050371 - 21 Apr 2021

Cited by 19 | Viewed by 4444

Abstract

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable [...] Read more.

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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37 pages, 1788 KiB

Open AccessReview

Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

by Veronika Kotrasová, Barbora Keresztesová, Gabriela Ondrovičová, Jacob A. Bauer, Henrieta Havalová, Vladimír Pevala, Eva Kutejová and Nina Kunová

Life 2021, 11(2), 82; https://doi.org/10.3390/life11020082 - 23 Jan 2021

Cited by 16 | Viewed by 6592

Abstract

The major role of mitochondria is to provide cells with energy, but no less important are their roles in responding to various stress factors and the metabolic changes and pathological processes that might occur inside and outside the cells. The post-translational modification of [...] Read more.

The major role of mitochondria is to provide cells with energy, but no less important are their roles in responding to various stress factors and the metabolic changes and pathological processes that might occur inside and outside the cells. The post-translational modification of proteins is a fast and efficient way for cells to adapt to ever changing conditions. Phosphorylation is a post-translational modification that signals these changes and propagates these signals throughout the whole cell, but it also changes the structure, function and interaction of individual proteins. In this review, we summarize the influence of kinases, the proteins responsible for phosphorylation, on mitochondrial biogenesis under various cellular conditions. We focus on their role in keeping mitochondria fully functional in healthy cells and also on the changes in mitochondrial structure and function that occur in pathological processes arising from the phosphorylation of mitochondrial proteins. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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22 pages, 854 KiB

Open AccessReview

Natural and Artificial Mechanisms of Mitochondrial Genome Elimination

by Elvira G. Zakirova, Vladimir V. Muzyka, Ilya O. Mazunin and Konstantin E. Orishchenko

Life 2021, 11(2), 76; https://doi.org/10.3390/life11020076 - 20 Jan 2021

Cited by 4 | Viewed by 3578

Abstract

The generally accepted theory of the genetic drift of mitochondrial alleles during mammalian ontogenesis is based on the presence of a selective bottleneck in the female germline. However, there is a variety of different theories on the pathways of genetic regulation of mitochondrial [...] Read more.

The generally accepted theory of the genetic drift of mitochondrial alleles during mammalian ontogenesis is based on the presence of a selective bottleneck in the female germline. However, there is a variety of different theories on the pathways of genetic regulation of mitochondrial DNA (mtDNA) dynamics in oogenesis and adult somatic cells. The current review summarizes present knowledge on the natural mechanisms of mitochondrial genome elimination during mammalian development. We also discuss the variety of existing and developing methodologies for artificial manipulation of the mtDNA heteroplasmy level. Understanding of the basics of mtDNA dynamics will shed the light on the pathogenesis and potential therapies of human diseases associated with mitochondrial dysfunction. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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42 pages, 2508 KiB

Open AccessEditor’s ChoiceReview

The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes

by James Chapman, Yi Shiau Ng and Thomas J. Nicholls

Life 2020, 10(9), 164; https://doi.org/10.3390/life10090164 - 26 Aug 2020

Cited by 42 | Viewed by 6184

Abstract

Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several [...] Read more.

Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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