Human Mitochondrial Stress-driven Obesity Resistance

NCT06080568 | Completed

• 1 other identifier: MITO-OB-RES
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The overarching aim of this observational study is to determine alterations in energy balance while exploring the underlying cellular mechanisms in human genetic models of mitochondrial stress. In a case-control design, individuals with pathogenic mitochondrial DNA mutations will be compared to healthy controls matched for sex, age, and physical activity level. Participants will attend a screening visit and an experimental trial including assessments of energy expenditure, appetite sensation, energy intake, and muscle and subcutaneous adipose tissue biopsy samples.

Conditions

Mitochondrial Diseases; Mitochondrial Myopathies; Mitochondrial Disorder

Keywords

Energy balance; Energy expenditure; Appetite; Energy intake; Mitochondrial dysfunction

Outcome Measures

Primary Outcomes (3)

• Resting energy expenditure

  Resting energy expenditure is measured in the fasting and fed state by indirect calorimetry

  Before (baseline) and 60-180 minutes after ingestion of a glucose solution

• Appetite

  Subjective appetite sensations are measured in the fasting and fed state by visual analogue scale (VAS) ratings

  Before (baseline) and 60-180 minutes after ingestion of a glucose solution as well as immediately after an ad libitum meal test

• Energy intake

  Energy intake is measured by quantifying the amount of food ingested during an ad libitum meal test

  180 minutes after ingestion of a glucose solution

Secondary Outcomes (5)

• Plasma hormones and cytokines modulating appetite and energy expenditure

  Before (baseline) and 0-180 minutes after ingestion of a glucose solution

• Plasma adipokines modulating appetite and energy expenditure

  Baseline

• Muscle mitochondrial leak respiration

  Baseline

• Muscle mitochondrial efficiency

  Baseline

• Muscle mitochondrial membrane potential

  Baseline

Other Outcomes (4)

• Body composition

  Baseline

• Physical activity level

  Baseline

• Self-reported physical activity

  Baseline

Study Arms (2)

Mitochondrial myopathy

Individuals with pathogenic mtDNA mutations

Control

Individuals without mtDNA mutations

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals with mitochondrial myopathy due to pathogenic mtDNA mutations are identified and recruited from the Copenhagen Neuromuscular Center or the Department of Clinical Genetics (Rigshospitalet). Control volunteers are recruited via recruitment announcements in Denmark.

You may qualify if:

• \- Known mtDNA point mutations

You may not qualify if:

• Use of antiarrhythmic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
• Diagnosed severe heart disease, dysregulated thyroid gland conditions, or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures.
• Pregnancy
• Eligibility criteria for controls
• Current and regular use of antidiabetic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
• Diagnosed heart disease, symptomatic asthma, liver cirrhosis or -failure, chronic kidney disease, dysregulated thyroid gland conditions or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures
• Daily use of tobacco products
• Excessive alcohol consumption
• Pregnancy

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• University of Copenhagen: collaborator

Study Sites (1)

Rigshospitalet

Copenhagen, Denmark, 2100, Denmark

Location

Related Publications (5)

• Guo Q, Xu Z, Zhou D, Fu T, Wang W, Sun W, Xiao L, Liu L, Ding C, Yin Y, Zhou Z, Sun Z, Zhu Y, Zhou W, Jia Y, Xue J, Chen Y, Chen XW, Piao HL, Lu B, Gan Z. Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4. Sci Adv. 2022 Jul 29;8(30):eabo0340. doi: 10.1126/sciadv.abo0340. Epub 2022 Jul 27.

  PMID: 35895846 BACKGROUND

• Yang M, Xu L, Xu C, Cui Y, Jiang S, Dong J, Liao L. The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients. Front Endocrinol (Lausanne). 2021 Nov 25;12:728043. doi: 10.3389/fendo.2021.728043. eCollection 2021.

  PMID: 34899594 BACKGROUND

• Sturm G, Karan KR, Monzel AS, Santhanam B, Taivassalo T, Bris C, Ware SA, Cross M, Towheed A, Higgins-Chen A, McManus MJ, Cardenas A, Lin J, Epel ES, Rahman S, Vissing J, Grassi B, Levine M, Horvath S, Haller RG, Lenaers G, Wallace DC, St-Onge MP, Tavazoie S, Procaccio V, Kaufman BA, Seifert EL, Hirano M, Picard M. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Commun Biol. 2023 Jan 12;6(1):22. doi: 10.1038/s42003-022-04303-x.

  PMID: 36635485 BACKGROUND

• O'Rahilly S. "Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture. Diabetes. 2021 Jan;70(1):29-38. doi: 10.2337/dbi19-0037.

  PMID: 33355307 BACKGROUND

• Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017 Apr 12;544(7649):235-239. doi: 10.1038/nature22034.

  PMID: 28406212 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood, muscle tissue, subcutaneous adipose tissue

MeSH Terms

Conditions

Mitochondrial Diseases; Mitochondrial Myopathies

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases

Study Officials

• Matteo Fiorenza, Ph.D.

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

• John Vissing, MD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

• Signe Torekov, Ph.D.

  University of Copenhagen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 29, 2023
• First Posted: October 12, 2023
• Study Start: October 20, 2023
• Primary Completion: December 20, 2024
• Study Completion: December 20, 2024
• Last Updated: June 22, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)