Bioinformatics in mitochondrial research

Mitochondria, with their unique genome separate from nuclear DNA, play a pivotal role in cellular bioenergetics and are central to numerous biological processes. Leveraging Next-Generation Sequencing (NGS) technologies and advanced bioinformatics, researchers can now analyse mitochondrial DNA (mtDNA) with unmatched precision, identifying mutations, structural changes, and variations that influence cellular function. The complexity of mitochondrial research, driven by the heterogeneity of these organelles across cells and tissues, is effectively addressed through NGS bioinformatics, providing insights into mitochondrial subpopulations and their genetic signatures.

Dissecting Mitochondrial Heterogeneity

Mitochondrial heterogeneity, the existence of diverse mitochondrial populations within the same cell or tissue, adds complexity to mitochondrial research. Through NGS bioinformatics, researchers can:

  • Identify mitochondrial subpopulations with unique genetic signatures.

  • Uncover how mitochondrial diversity impacts functions such as energy metabolism and cellular signalling.

By analysing these subpopulations, bioinformatics helps unravel the specific contributions of different mitochondrial genomes, offering a deeper understanding of their roles in health and disease.

Variant Analysis in Mitochondrial DNA

NGS bioinformatics is instrumental in identifying genetic variants within the mitochondrial genome. This includes precise detection of:

  • Single nucleotide variants (SNVs)

  • Insertions and deletions (indels)

  • Structural variations that affect the integrity of the mitochondrial genome.

These tools provide a comprehensive view of how genetic alterations in mtDNA contribute to various mitochondrial disorders. Such disorders often manifest as issues with energy metabolism, impacting tissues with high energy demands like the heart, muscles, and brain. By uncovering these variations, bioinformatics enables researchers to link specific mutations with disease phenotypes and potential therapeutic targets.

Heteroplasmy Detection

A unique feature of mitochondrial genetics is heteroplasmy, where different versions of the mitochondrial genome coexist within a cell. NGS bioinformatics excels in detecting and quantifying heteroplasmy, offering insights into:

  • The relative abundance of different mtDNA alleles.

  • How shifts in heteroplasmy levels influence cellular function and disease progression.

Understanding heteroplasmy is critical for exploring the dynamics of mitochondrial populations and their role in developing conditions such as neuromuscular disorders, cardiomyopathies, and neurodegenerative diseases. NGS-based bioinformatics offers the resolution to detect even low-frequency alleles, ensuring a complete picture of mitochondrial diversity within tissues.

Unraveling Mitochondrial Disease Mechanisms

Mitochondrial research is essential for understanding the underlying mechanisms of mitochondrial diseases, often caused by mtDNA mutations or structural rearrangements. By using bioinformatics in conjunction with NGS, researchers can:

  • Characterise the genetic landscape of mitochondrial disorders.

  • Investigate the impact of specific mutations on energy production and cellular signalling pathways.

This precise genetic mapping is invaluable for developing therapeutic strategies targeting the root causes of mitochondrial dysfunction, including gene therapies and other interventions to correct or compensate for mtDNA defects.

NGS bioinformatics has become indispensable in mitochondrial research, offering the tools necessary to decode the complexity of the mitochondrial genome. From variant analysis and heteroplasmy detection to exploring the functional consequences of mtDNA mutations, bioinformatics empowers researchers to make critical discoveries that pave the way for novel therapies and a deeper understanding of mitochondrial biology.

Selection of our publications:

Van Haute L, et al. (2023) TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease. Nat Commun doi: 10.1038/s41467-023-36277-7

Van Haute L, et al. (2021) Detection of 5-formylcytosine in mitochondrial transcriptome. Methods Mol Biol 2192:59-68

Van Haute L, et al. (2019) METTL15 introduces N4-methylcytidine into human mitochondrial 12S rRNA and is required for mitoribosome biogenesis. Nucleic Acids Res 47(19):10267-10281

Van Haute L, et al. (2019) NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs. Nucleic Acids Res 47(16):8720-8733

Van Haute L, et al. (2017) Dealing with an unconventional genetic code in mitochondria: the biogenesis and pathogenic defects of the 5-formylcytosine modification in mitochondrial tRNAMet. Biomolecules 7(1):24

Van Haute L, et al. (2016) Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun 7:12039

Van Haute L, et al. (2015) Mitochondrial transcript maturation and its disorders. J Inherit Metab Dis 38:655-80

Van Haute L, et al. (2013) Human embryonic stem cells commonly display large mitochondrial DNA deletions. Nat Biotechnol 31:20-3