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Last update 08 May 2025

Multiple Mitochondrial Dysfunctions Syndrome

Last update 08 May 2025

Basic Info

Synonyms

MMDS - multiple mitochondrial dysfunctions syndrome, Multiple Mitochondrial Dysfunctions Syndrome, Multiple mitochondrial dysfunctions syndrome

+ [2]

Introduction

Syndrome caused by impairment of mitochondria. Whilst mitochondrial disorders may be caused by impairment of a single stage of energy production, individuals with multiple mitochondrial dysfunctions syndrome have reduced function of more than one stage. Symptoms begin in early life and affected individuals usually do not live past infancy. Symptoms include encephalopathy, hypotonia, seizures and psychomotor delay. Most affected babies have lactic acidosis that can be life threatening.

Drugs associated with Multiple Mitochondrial Dysfunctions Syndrome

MiD49

Target

DNM1L

Mechanism

DNM1L inhibitors

Active Org.

Mitobridge, Inc.

Originator Org.

Mitobridge, Inc.

Active Indication

Multiple Mitochondrial Dysfunctions Syndrome

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

KF-52

Target

PFKM

Mechanism

PFKM inhibitors

Active Org.

Kansai University

Originator Org.

Kansai University

Active Indication

Acidosis, Lactic [+1]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Multiple Mitochondrial Dysfunctions Syndrome

NCT06080581

/ RecruitingNot ApplicableIIT

Mitochondrial Derangements Driving Muscle Insulin Resistance in Humans

The overarching aim of this observational study is to characterize muscle mitochondrial defects in individuals harboring pathogenic mitochondrial DNA (mtDNA) mutations associated with an insulin-resistant phenotype.
In a case-control design, individuals with pathogenic mtDNA mutations will be compared to controls matched for sex, age, and physical activity level. Participants will attend a screening visit and two experimental trials including:
* An oral glucose tolerance test
* A hyperinsulinemic-euglycemic clamp combined with measurements of femoral artery blood flow and arteriovenous difference of glucose
* Muscle biopsy samples

Start Date20 Oct 2023

Sponsor / Collaborator

Rigshospitalet

[+1]

NCT01439854

/ CompletedNot ApplicableIIT

Regulation of Hepatic and Peripheral Glucose Metabolism: Protocol IVA. Effect of Plasma Glucose Reduction by Selective SLGT2 Inhibition on Mitochondrial Dysfunction and Impaired Insulin Signaling/Sensitivity in T2DM

The purpose of this study is to examine the effect of the chronic treatment of type 2 diabetes (T2DM) with dapagliflozin on: (1) mitochondrial gene function/expression and insulin signaling/action and (2) oral glucose tolerance and beta cell function. Dapagliflozin is a potent, highly specific inhibitor of renal glucose transport [SGLT2].

Start Date01 Mar 2011

Sponsor / Collaborator

University of Texas Health Science Center At San Antonio

[+1]

100 Clinical Results associated with Multiple Mitochondrial Dysfunctions Syndrome

100 Translational Medicine associated with Multiple Mitochondrial Dysfunctions Syndrome

0 Patents (Medical) associated with Multiple Mitochondrial Dysfunctions Syndrome

107

Literatures (Medical) associated with Multiple Mitochondrial Dysfunctions Syndrome

01 Jun 2025·Molecular Genetics and Metabolism

Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis

Article

Author: Ohtake, Akira ; Kishita, Yoshihito ; Sugiura, Ayumu ; Shimura, Masaru ; Imai-Okazaki, Atsuko ; Iijima, Hiroyuki ; Murayama, Kei ; Okazaki, Yasushi

BOLA3 is one of the proteins involved in the assembly and transport of [4Fe-4S] clusters, which are incorporated into mitochondrial respiratory chain complexes I and II, aconitase, and lipoic acid synthetase. Pathogenic variants in the BOLA3 gene cause a rare condition known as multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, characterized by life-threatening lactic acidosis, nonketotic hyperglycinemia, and hypertrophic cardiomyopathy. The aim of this study was to elucidate the biochemical characteristics of patients with BOLA3 variants and to clarify the role of BOLA3 protein in humans. The characteristics, clinical course, and biochemical data of eight Japanese patients with BOLA3 pathogenic variants were collected. In addition, metabolomic analyses were performed using capillary electrophoresis time-of-flight mass spectrometry, blue native polyacrylamide gel electrophoresis (BN-PAGE)/Western blot analysis of mitochondrial respiratory chain complexes, and in-gel enzyme staining of mitochondrial respiratory chain complexes of fibroblasts from all eight patients. Metabolomic data were compared between the eight patients with BOLA3 variants and three control samples using Welch's t-test. In the metabolomic analysis, levels of lactic acid, pyruvic acid, alanine, tricarboxylic acid (TCA) cycle intermediates (such as α-ketoglutaric acid and succinic acid), branched-chain amino acids, and metabolites of lysine and tryptophan were significantly elevated in the BOLA3 group. Data collected during the patients' lives showed increased lactic acid and glycine levels. In BN-PAGE/Western blot analysis and in-gel enzyme staining, bands for complexes I and II were barely detectable in all eight cases. These results indicate that BOLA3 variants decrease the activity of lipoic acid-dependent proteins (pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, branched-chain ketoacid dehydrogenase, and the glycine cleavage system), as well as mitochondrial respiratory chain complexes I and II, but do not affect aconitase. Thus, it is believed that BOLA3 is involved in transporting [4Fe-4S] clusters to respiratory chain complexes I and II and lipoic acid synthetase, but does not interfere with aconitase. These findings suggest that while lipoic acid supplementation or vitamin cocktails may provide benefits, the impaired [4Fe-4S] cluster pathway itself should be targeted for treatment to improve the extensive metabolic abnormalities caused by BOLA3 deficiency.

01 May 2025·Biochemical and Biophysical Research Communications

Yeast models of mutations in NFU1 gene for biochemical characterization and drug screening

Article

Author: Zhou, Hua ; Liu, Yi ; Liu, Siru ; Cai, Heng ; Fan, Wanyan

The mutations in the NFU1 gene result in the autosomal recessive hereditary disorder known as Multiple Mitochondrial Dysfunction Syndrome 1 (MMDS1). Pathogenic mutations cause the intra-mitochondrial target proteins of NFU1 (known as Nfu1 in yeast) to become dysfunctional. There have been reports of 20 NFU1 mutations to date, however the precise pathogenic mechanism of MMDS1 is yet unknown. In this study, we simulated the missense mutations identified in patients and constructed four yeast models to confirm the pathogenic relevance of these mutations in humans. We analyzed the mitochondrial phenotype of yeast cells, including their respiration and oxidative stress. Mutated yeast strains exhibited a higher frequency of small colony formation, suggesting enhanced mutability of mtDNA. There are differences in the effects of mutations at different sites on cells, and their severity may be related to the CxxC motif. Finally, we established an efficient, yeast-based method to select drugs capable of alleviating oxidative stress caused by NFU1 mutations. These yeast models are useful for studying the pathogenic association of novel mutations or rare polymorphisms in NFU1, which will provide theoretical guidance for treating MMDS1 disease or other mitochondrial diseases.

10 Jan 2025·Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics

[Clinical characteristics and genetic analysis of two children with Multiple mitochondrial dysfunction syndrome due to variants of IBA57 gene].

Article

Author: Chen, Shan ; Wu, Qiuping ; Li, Jingjing ; Liu, Lijuan ; Wen, Xiangshu

OBJECTIVETo investigate the clinical features and genetic variants associated with Multiple mitochondrial dysfunction syndrome (MMDS) type 3 in two children.METHODSTwo children diagnosed with MMDS type 3 at Zhuhai Maternal and Child Health Care Hospital in January 2021 were selected for this study. A retrospective analysis of their clinical data was carried out. Whole exome sequencing was conducted on the two children and their parents, followed by Sanger sequencing for candidate variants and bioinformatic analysis. Both children received comprehensive rehabilitative therapy and were followed up for 3 years. This study was approved by the Ethics Committee of Zhuhai Maternal and Child Health Hospital (Ethics No. 202380).RESULTSThe two MMDS type 3 children were monozygotic twin girls, aged 9 months, presenting with developmental regression, pyramidal signs, and other clinical manifestations. Cranial MRI revealed widespread abnormal signals and vacuolar changes in the white matter. Whole exome sequencing revealed that both children had harbored compound heterozygous variants of the IBA57 gene, namely c.286T>C (p.Tyr96His) and c.307C>T (p.Gln103Ter). Sanger sequencing confirmed that these variants were inherited from their father and mother, respectively. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, both variants were classified as pathogenic (PM2_Supporting+PM3_Very Strong+PP3_Moderate; PVS1+PM2_Supporting+PM3). After treatment with vitamins, levocarnitine, ATP, coenzyme Q10, and other drugs, both children showed partial recovery of neurodevelopmental regression, with improvement in feeding and sleep. Over the 3-year follow-up, there was slow but progressive improvement in motor, language, and cognitive development.CONCLUSIONThe compound heterozygous variants c.286T>C (p.Tyr96His) and c.307C>T (p.Gln103Ter) of the IBA57 gene probably underlay the MMDS type 3 in the twin pair. Clinicians should be vigilant about the possibility of MMDS type 3 in children with neurodevelopmental regression and early cranial MRI findings indicating widespread white matter abnormalities with vacuolar changes, as these may be indicative of IBA57 gene variants.

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