Mitochondrial threshold effects

The study of mitochondrial diseases has revealed dramatic variability in the phenotypic presentation of mitochondrial genetic defects. To attempt to understand this variability, different authors have studied energy metabolism in transmitochondrial cell lines carrying different proportions of various pathogenic mutations in their mitochondrial DNA. The same kinds of experiments have been performed on isolated mitochondria and on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, phenotypic manifestation of the genetic defect occurs only when a threshold level is exceeded, and this phenomenon has been named the ‘phenotypic threshold effect'. Subsequently, several authors showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the ‘biochemical threshold effect'. More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a ‘translational threshold effect'. In this review these different mitochondrial threshold effects are discussed, along with their molecular bases and the roles that they play in the presentation of mitochondrial diseases.

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Respiratory-deficient human fibroblasts exhibiting defective mitochondrial DNA replication

Biochemical Journal ◽

10.1042/bj3050817 ◽

1995 ◽

Vol 305 (3) ◽

pp. 817-822 ◽

Cited By ~ 25

Author(s):

A G Bodnar ◽

J M Cooper ◽

J V Leonard ◽

A H V Schapira

Keyword(s):

Mitochondrial Dna ◽

Respiratory Chain ◽

Cultured Cells ◽

Human Fibroblasts ◽

Genetic Defect ◽

Mitochondrial Protein ◽

Mitochondrial Respiratory Chain ◽

Human Cell Line ◽

Respiratory Chain Complexes ◽

Respiratory Deficient

We have characterized cultured skin fibroblasts from two siblings affected with a fatal mitochondrial disease caused by a nuclear genetic defect. Mitochondrial respiratory-chain function was severely decreased in these cells. Southern-blot analysis showed that the fibroblasts had reduced levels of mitochondrial DNA (mtDNA). The mtDNA was unstable and was eliminated from the cultured cells over many generations, generating the rho0 genotype. As the mtDNA level decreased, the cells became more dependent upon pyruvate and uridine for growth. Nuclear-encoded subunits of respiratory-chain complexes were synthesized and imported into the mitochondria of the mtDNA-depleted cells, albeit at reduced levels compared with the controls. Mitochondrial protein synthesis directed by the residual mtDNA indicated that the mtDNA was expressed and that the defect specifically involves the replication or maintenance of mtDNA. This is a unique example of a respiratory-deficient human cell line exhibiting defective mtDNA replication.

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Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM

Frontiers in Physiology ◽

10.3389/fphys.2021.715485 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anna-Lena Forst ◽

Markus Reichold ◽

Robert Kleta ◽

Richard Warth

Keyword(s):

Mitochondrial Protein ◽

Mitochondrial Diseases ◽

Atp Synthesis ◽

Inflammasome Activation ◽

Renal Fanconi Syndrome ◽

Nephron Segment ◽

Transport Defect ◽

Mitochondrial Pathology ◽

Proximal Tubular ◽

Complex Signaling

The mitochondria of the proximal tubule are essential for providing energy in this nephron segment, whose ATP generation is almost exclusively oxygen dependent. In addition, mitochondria are involved in a variety of metabolic processes and complex signaling networks. Proximal tubular mitochondrial dysfunction can therefore affect renal function in very different ways. Two autosomal dominantly inherited forms of renal Fanconi syndrome illustrate how multifaceted mitochondrial pathology can be: Mutation of EHHADH, an enzyme in fatty acid metabolism, results in decreased ATP synthesis and a consecutive transport defect. In contrast, mutations of GATM, an enzyme in the creatine biosynthetic pathway, leave ATP synthesis unaffected but do lead to mitochondrial protein aggregates, inflammasome activation, and renal fibrosis with progressive renal failure. In this review article, the distinct pathophysiological mechanisms of these two diseases are presented, which are examples of the spectrum of proximal tubular mitochondrial diseases.

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Effect of ‘binary mitochondrial heteroplasmy’ on respiration and ATP synthesis: implications for mitochondrial diseases

Biochemical Journal ◽

10.1042/bj3570835 ◽

2001 ◽

Vol 357 (3) ◽

pp. 835-842 ◽

Cited By ~ 6

Author(s):

Bernard KORZENIEWSKI ◽

Monique MALGAT ◽

Thierry LETELLIER ◽

Jean-Pierre MAZAT

Keyword(s):

Mitochondrial Dna ◽

Oxidative Phosphorylation ◽

Respiratory Chain ◽

Energy Demand ◽

Phenotypic Expression ◽

Chain Complex ◽

Mitochondrial Diseases ◽

Respiratory Chain Complex ◽

Mitochondrial Heteroplasmy ◽

Partial Deficiency

Respiratory-chain-complex subunits in mitochondria are encoded by nuclear or mitochondrial DNA. This property might have profound implications for the phenotypic expression of mutations affecting oxidative phosphorylation complexes. The aim of this paper is to study the importance of the origin of the mutation (nuclear or mitochondrial) on the expression of mitochondrial defects. We have therefore developed theoretical models illustrating three mechanisms of nuclear or mitochondrial DNA mutation giving rise to a deficiency in the respiratory-chain complex: (1) a partial deficiency, homogeneously distributed in all of the mitochondria; (2) a complete deficiency, only affecting some of the mitochondria (‘binary mitochondrial heteroplasmy’); and (3) a partial deficiency, affecting only some of the mitochondria. We show that mutations affecting oxidative phosphorylation complexes will be expressed in different ways depending on their origins. Although the expression of nuclear or mitochondrial mutations is evidence of a biochemical threshold, we demonstrate that the threshold value depends on the origin and distribution of the mutation (homogeneous or not) and also on the energy demand of the tissue. This last prediction has been confirmed in an experimental model using hexokinase for the simulation of the energy demand and a variation in mitochondrial concentration. We also emphasize the possible role of ‘binary mitochondrial heteroplasmy’ in the expression of mitochondrial DNA mutations and thus the importance of the origin of the deficit (mutation) for the diagnosis or therapy of mitochondrial diseases.

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Nonneutral Mitochondrial DNA Variation in Humans and Chimpanzees

Genetics ◽

10.1093/genetics/142.3.953 ◽

1996 ◽

Vol 142 (3) ◽

pp. 953-963 ◽

Cited By ~ 4

Author(s):

Michael W Nachman ◽

Wesley M Brown ◽

Mark Stoneking ◽

Charles F Aquadro

Keyword(s):

Mitochondrial Dna ◽

Sequence Data ◽

Mitochondrial Protein ◽

Mitochondrial Diseases ◽

Neutral Model ◽

Nucleotide Substitutions ◽

Dna Variation ◽

Mtdna Sequence ◽

Restriction Sites ◽

Complete Mtdna

Abstract We sequenced the NADH dehydrogenase subunit 3 (ND3) gene from a sample of 61 humans, five common chimpanzees, and one gorilla to test whether patterns of mitochondrial DNA (mtDNA) variation are consistent with a neutral model of molecular evolution. Within humans and within chimpanzees, the ratio of replacement to silent nucleotide substitutions was higher than observed in comparisons between species, contrary to neutral expectations. To test the generality of this result, we reanalyzed published human RFLP data from the entire mitochondrial genome. Gains of restriction sites relative to a known human mtDNA sequence were used to infer unambiguous nucleotide substitutions. We also compared the complete mtDNA sequences of three humans. Both the RFLP data and the sequence data reveal a higher ratio of replacement to silent nucleotide substitutions within humans than is seen between species. This pattern is observed at most or all human mitochondrial genes and is inconsistent with a strictly neutral model. These data suggest that many mitochondrial protein polymorphisms are slightly deleterious, consistent with studies of human mitochondrial diseases.

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Mobilization of Adenine Nucleotide Translocators as Molecular Bases of the Biochemical Threshold Effect Observed in Mitochondrial Diseases

Journal of Biological Chemistry ◽

10.1074/jbc.m314259200 ◽

2004 ◽

Vol 279 (19) ◽

pp. 20411-20421 ◽

Cited By ~ 37

Author(s):

Benjamin Faustin ◽

Rodrigue Rossignol ◽

Christophe Rocher ◽

Giovanni Bénard ◽

Monique Malgat ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Conformational Changes ◽

Adenine Nucleotide ◽

Mitochondrial Diseases ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Threshold Effect ◽

Adenine Nucleotide Translocator ◽

Flux Increase ◽

Molecular Bases

The existence of a biochemical threshold effect in the metabolic expression of oxidative phosphorylation deficiencies has considerable implications for the understanding of mitochondrial bioenergetics and the study of mitochondrial diseases. However, the molecular bases of this phenomenon remain unclear. We report here a new mechanism to explain this threshold effect, based on a reserve of enzymes not initially participating in the respiratory rate that can be activated either to respond to a flux increase or to compensate for a defect induced by a mutation. We show that this mobilization occurs through 1) the assembly of inactive adenine nucleotide translocator isoform 1 subunits into oligomeric active carriers or 2) conformational changes in the adenine nucleotide translocator isoform 1 in a permeability transition pore-like structure. We discuss how these transitions are sensitive to the steady state of oxidative phosphorylation functioning or tissue and analyze their consequences on the threshold effect.

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A Clinical-Based Diagnostic Approach to Cerebellar Atrophy in Children

Applied Sciences ◽

10.3390/app11052333 ◽

2021 ◽

Vol 11 (5) ◽

pp. 2333

Author(s):

Claudia Ciaccio ◽

Chiara Pantaleoni ◽

Franco Taroni ◽

Daniela Di Bella ◽

Stefania Magri ◽

...

Keyword(s):

Muscle Biopsy ◽

Single Gene ◽

Brain Mri ◽

Genetic Defect ◽

Cerebellar Atrophy ◽

Chain Complex ◽

Clinical Findings ◽

Diagnostic Workup ◽

Diagnostic Approach ◽

Disease Definition

Background: Cerebellar atrophy is a neuroradiological definition that categorizes conditions heterogeneous for clinical findings, disease course, and genetic defect. Most of the papers proposing a diagnostic workup for pediatric ataxias are based on neuroradiology or on the literature and experimental knowledge, with a poor participation of clinics in the process of disease definition. Our study aims to offer a different perspective on the way we approach cerebellar atrophy in developmental age, building a clinical-based diagnostic workup to guide molecular diagnosis. Methods: we recruited 52 patients with pediatric-onset cerebellar atrophy and definite disease categorization. Children underwent brain MRI, neurophysiological exams, metabolic investigations, and muscle biopsy with respiratory chain complex study. Single-gene sequencing, next-generation sequencing NGS panels, whole-exome sequencing (WES), and disease-specific techniques have been used to reach genetic confirmation. Results: Brain MRI is the main method of diagnosis, followed by tests on muscle biopsy and peripheral nervous system study. Other exams (e.g., metabolic investigations or evoked potentials) may be useful to narrow the list of diagnostic possibilities. Conclusions: We propose a diagnostic approach to cerebellar atrophy in children based on clinical findings, and support the evidence that a precise phenotypic definition may lead to the formulation of a definite diagnosis or otherwise guide the back phenotyping process derived from large molecular data.

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Mitochondrial microRNAs: A Putative Role in Tissue Regeneration

Biology ◽

10.3390/biology9120486 ◽

2020 ◽

Vol 9 (12) ◽

pp. 486

Author(s):

Sílvia C. Rodrigues ◽

Renato M. S. Cardoso ◽

Filipe V. Duarte

Keyword(s):

Tissue Regeneration ◽

Protein Complexes ◽

Mitochondrial Protein ◽

Noncoding Rnas ◽

Atp Synthesis ◽

Mitochondrial Proteins ◽

Cellular Mechanisms ◽

Small Noncoding Rnas ◽

Mitochondrial Ribosome

The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.

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Threshold Effects of Infectious Disease Outbreaks on Livestock Prices: Cases of African Swine Fever and Avian Influenza in South Korea

Applied Sciences ◽

10.3390/app11115114 ◽

2021 ◽

Vol 11 (11) ◽

pp. 5114

Author(s):

Hyung-Chul Rah ◽

Hyeon-Woong Kim ◽

Aziz Nasridinov ◽

Wan-Sup Cho ◽

Seo-Hwa Choi ◽

...

Keyword(s):

Avian Influenza ◽

Infectious Diseases ◽

Disease Outbreaks ◽

African Swine Fever ◽

Threshold Effect ◽

Impact Response ◽

Threshold Effects ◽

Infectious Disease Outbreaks ◽

Retail Prices ◽

The Impact

In this paper we demonstrate the threshold effects of infectious diseases on livestock prices. Daily retail prices of pork and chicken were used as structured data; news and SNS mentions of African Swine Fever (ASF) and Avian Influenza (AI) were used as unstructured data. Models were tested for the threshold effects of disease-related news and SNS frequencies, specifically those related to ASF and AI, on the retail prices of pork and chicken, respectively. The effects were found to exist, and the values of ASF-related news on pork prices were estimated to be −9 and 8, indicating that the threshold autoregressive (TAR) model can be divided into three regimes. The coefficients of the ASF-related SNS frequencies on pork prices were 1.1666, 0.2663 and −0.1035 for regimes 1, 2 and 3, respectively, suggesting that pork prices increased by 1.1666 Korean won in regime 1 when ASF-related SNS frequencies increased. To promote pork consumption by SNS posts, the required SNS frequencies were estimated to have impacts as great as one standard deviation in the pork price. These values were 247.057, 1309.158 and 2817.266 for regimes 1, 2 and 3, respectively. The impact response periods for pork prices were estimated to last 48, 6, and 8 days for regimes 1, 2 and 3, respectively. When the prediction accuracies of the TAR and autoregressive (AR) models with regard to pork prices were compared for the root mean square error, the prediction accuracy of the TAR model was found to be slightly better than that of the AR. When the threshold effect of AI-related news on chicken prices was tested, a linear relationship appeared without a threshold effect. These findings suggest that when infectious diseases such as ASF occur for the first time, the impact on livestock prices is significant, as indicated by the threshold effect and the long impact response period. Our findings also suggest that the impact on livestock prices is not remarkable when infectious diseases occur multiple times, as in the case of AI. To date, this study is the first to suggest the use of SNS to promote meat consumption.

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Mitochondrial DNA Replacement Techniques to Prevent Human Mitochondrial Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22020551 ◽

2021 ◽

Vol 22 (2) ◽

pp. 551

Author(s):

Luis Sendra ◽

Alfredo García-Mares ◽

María José Herrero ◽

Salvador F. Aliño

Keyword(s):

Mitochondrial Dna ◽

Nuclear Dna ◽

Genetic Disorders ◽

Mitochondrial Diseases ◽

Legal Regulation ◽

Donor Oocyte ◽

Legal Position ◽

Ethical And Legal Issues ◽

Mitochondrial Replacement Techniques ◽

Do So

Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required.

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Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction

Molecular and Cellular Biology ◽

10.1128/mcb.2.1.30-41.1982 ◽

1982 ◽

Vol 2 (1) ◽

pp. 30-41

Author(s):

N A Oliver ◽

D C Wallace

Keyword(s):

Mitochondrial Dna ◽

Restriction Site ◽

Mitochondrial Protein ◽

Mitochondrial Protein Synthesis ◽

Human Mitochondrial Dna ◽

Ht1080 Cells ◽

Mitochondrial Dnas ◽

A Cell ◽

Dna Restriction ◽

Restriction Site Polymorphisms

Two mitochondrially synthesized marker polypeptides, MV-1 and MV-2, were found in human HeLa and HT1080 cells. These were assigned to the mitochondrial DNA in HeLa-HT1080 cybrids and hybrids by demonstrating their linkage to cytoplasmic genetic markers. These markers include mitochondrial DNA restriction site polymorphisms and resistance to chloramphenicol, an inhibitor of mitochondrial protein synthesis. In the absence of chloramphenicol, the expression of MV-1 and MV-2 in cybrids and hybrids was found to be directly proportional to the ratio of the parental mitochondrial DNAs. In the presence of chloramphenicol, the marker polypeptide linked to the chloramphenicol-sensitive mitochondrial DNA continued to be expressed. This demonstrated that resistant and sensitive mitochondrial DNAs can cooperate within a cell for gene expression and that the CAP-resistant allele was dominant or codominant to sensitive. Such cooperation suggests that mitochondrial DNAs can be exchanged between mitochondria.

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