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Mechanisms and regulation of human mitochondrial transcription

Nature Reviews Molecular Cell Biology volume 25, pages 119–132 (2024)Cite this article

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Abstract

The expression of mitochondrial genes is regulated in response to the metabolic needs of different cell types, but the basic mechanisms underlying this process are still poorly understood. In this Review, we describe how different layers of regulation cooperate to fine tune initiation of both mitochondrial DNA (mtDNA) transcription and replication in human cells. We discuss our current understanding of the molecular mechanisms that drive and regulate transcription initiation from mtDNA promoters, and how the packaging of mtDNA into nucleoids can control the number of mtDNA molecules available for both transcription and replication. Indeed, a unique aspect of the mitochondrial transcription machinery is that it is coupled to mtDNA replication, such that mitochondrial RNA polymerase is additionally required for primer synthesis at mtDNA origins of replication. We discuss how the choice between replication-primer formation and genome-length RNA synthesis is controlled at the main origin of replication (OriH) and how the recent discovery of an additional mitochondrial promoter (LSP2) in humans may change this long-standing model.

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Fig. 1: Organization of the human mitochondrial genome.
Fig. 2: Mitochondrial promoter recognition and initiation of transcription.
Fig. 3: H-strand mitochondrial DNA replication through RNA primer formation at origin of heavy-strand replication.
Fig. 4: Mitochondrial transcription patterns and the potential role of the second light-strand promoter.
Fig. 5: 7S RNA inhibits mitochondrial transcription initiation.
Fig. 6: Nucleoprotein formation by mitochondrial transcription factor A and the regulation of mitochondrial DNA activity.

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  1. Institute for Mitochondrial Diseases and Ageing, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Benedict G. Tan

  2. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

    Claes M. Gustafsson & Maria Falkenberg

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Tan, B.G., Gustafsson, C.M. & Falkenberg, M. Mechanisms and regulation of human mitochondrial transcription. Nat Rev Mol Cell Biol 25, 119–132 (2024). https://doi.org/10.1038/s41580-023-00661-4

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