Implementing a new variant load model to investigate the role of mtDNA in oxidative stress and inflammation in a bi-ethnic cohort: the SABPA study

Abstract

Mitochondrial DNA (mtDNA) variation has been implicated in several common complex and degenerative diseases, including cardiovascular disease. Inflammation is seen as part of many of these conditions. Mitochondria feature in inflammatory pathways and it has been suggested that mtDNA variation or released mtDNA might be important in this phenomenon. To determine if mtDNA is involved in the mechanisms leading up to cardiovascular disease, we investigated the role of these variants in seven indicators of oxidative stress and inflammation. This study was done in participants of the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) cohort, a South African bi-ethnic cohort (N = 363). We applied a variant load hypothesis, which is an alternative approach to, and moves away from the classic haplogroup association approaches, to evaluate the cumulative effect of non-synonymous mtDNA variants on measurements of serum peroxides, nitric oxide metabolites, 8-hydroxy-deoxyguanosine, thiobarbituric acid reactive substances, whole blood reduced glutathione, C-reactive protein, and tumor necrosis factor alpha. We found no significant relationships between non-synonymous mtDNA variants and the seven biochemical parameters investigated here. Non-synonymous mtDNA variants are unlikely to impact on disease in this cohort, to an appreciable or measurable extent.

Keywords:

• Mitochondrial DNA
• African
• inflammation
• oxidative stress
• MutPred score
• variant load

Acknowledgements

The authors acknowledge the Faculty of Natural Sciences of the North-West University for contributing to funding and Thermo Fisher South Africa for providing additional technical resources to this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Notes on contributors

Marianne Venter

Marianne Venter completed her PhD studies in Biochemistry at the North-West University (NWU), Potchefstroom Campus in 2017. She has been teaching Biochemistry at the NWU since 2011. Currently, she is a senior lecturer in Biochemistry at the NWU where her research is focused on mitochondrial bioenergetics, metabolism and genetics. Together with Dr Elson, she aims to develop new models to investigate the role of mitochondrial DNA (mtDNA) variants in common complex disease such as cardiovascular disease, Parkinson’s disease and chronic fatigue syndrome/myalgic encephalomyelitis. She is also interested in using metabolomics to better understand, characterize and diagnose mitochondrial disease. To do this she is currently using mitochondrial disease models to explore new methods of using metabolomics data in disease models.

Leone Malan

Leone Malan is a registered teacher and nurse and commenced with research in 2007. She holds the position of full professor at the North-West University (NWU), Potchefstroom Campus. She aims to underpin a mechanistic pathway pertaining brain-heart health (emotional stress, neural and adrenal fatigue, hypertension and endothelial dysfunction). With this focus in mind she designed the first well-controlled psychophysiological prospective cohort study in Sub Saharan Africa [SABPA: Sympathetic activity and Ambulatory Blood pressure in Africans]. She then conceptualized and implemented a Hypertension Research and Training clinic on-campus, inducing service delivery and cardiovascular monitoring programs including referrals to clinicians. Eventually she was inducted into the Forum University Nursing Deans in South Africa (FUNDISA) Hall of Fame for research excellence in Nursing, 2015. Apart from being on the council of the European Society of Cardiology on Hypertension, she holds various professional memberships. Output includes more than 100 international peer-reviewed articles, chapters in books, and invited editorials and commentaries. She has delivered more than 51 Honors, Master’s and PhD students. She and her extensive international expert and pharmaceutical stake holders’ network aim to develop a clinical diagnostic tool for preventive stress-related cardiomyopathy.

Joanna L. Elson

Joanna L. Elson is currently a senior lecturer in mitochondrial genetics and researcher at the Institute of Genetic Medicine (IGM) of Newcastle University. She also holds a position as extraordinary Professor at the North-West University, South Africa. A major theme in her research has been the use evolutionary concepts and computational methods to help in the assignment of pathogenicity to mtDNA variants in patients with clinically manifesting mitochondrial disease. Most recently she has explored the importance of haplogroup context in the expression and penetrance of mtDNA mutations. Another prominent theme of her research entails the role of mtDNA variation in complex traits. This area has been very controversial over the years, with a myriad of conflicting results to be found in the literature. She is developing new models to link mtDNA variation to complex traits. An emerging theme looks at the role of mitochondria and mtDNA in Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME). She has published over sixty original research articles in peer-reviewed journals. She has supervised more than 21 Master’s and PhD students.

Francois H. van der Westhuizen

Francois H. van der Westhuizen has been a lecturer in Biochemistry and researcher on mitochondrial function and disease since 1993 and holds the position of full professor at the North-West University (NWU), Potchefstroom Campus. His research focuses on the biochemical and genetic basis of diseases involving energy metabolism within context of the South African population. For this purpose, he set up the Mitochondria Research Laboratory in 2002, which is unique in South Africa and consists of a group of ∼15 people (academic and technical staff, post-docs and post graduate students) and a wide range of facilities. A primary objective of this laboratory is the biochemical and genetic identification and characterization of mitochondrial disease in South African patients. In this setting he studies various aspects of the disease, including better identification methods using metabolic biomarkers/biosignatures and South African population specific mutations. He also performs research using disease models to better understand mitochondrial disease and identify novel strategies to treat the redox imbalance that occurs in these diseases. A second objective of this laboratory is to study the involvement of energy metabolism in more common diseases, specifically cardiovascular disease, cancer and chronic fatigue syndrome/myalgic encephalomyelitis.