No role for nuclear transcription regulators in mammalian mitochondria?

• Published in: Molecular cell 2023-03, Vol.83 (6), p.832-842
• Main Authors: Rubalcava-Gracia, Diana, García-Villegas, Rodolfo, Larsson, Nils-Göran
• Format: Article
• Language: English
• Subjects: Animals; Cell Nucleus - genetics; Cell Nucleus - metabolism; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Mammals - genetics; Mammals - metabolism; Medicin och hälsovetenskap; Mitochondria - genetics; Mitochondria - metabolism; Nuclear Respiratory Factor 1 - metabolism
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2022.09.010

Although the mammalian mtDNA transcription machinery is simple and resembles bacteriophage systems, there are many reports that nuclear transcription regulators, as exemplified by MEF2D, MOF, PGC-1α, and hormone receptors, are imported into mammalian mitochondria and directly interact with the mtDNA transcription machinery. However, the supporting experimental evidence for this concept is open to alternate interpretations, and a main issue is the difficulty in distinguishing indirect regulation of mtDNA transcription, caused by altered nuclear gene expression, from direct intramitochondrial effects. We provide a critical discussion and experimental guidelines to stringently assess roles of intramitochondrial factors implicated in direct regulation of mammalian mtDNA transcription. The machinery for mammalian mtDNA transcription is distinct from the ones in the nucleus. Nevertheless, several controversial reports suggest that nuclear transcription regulators also localize to mitochondria to directly modulate mtDNA transcription. Rubalcava-Gracia et al. revisit the roles of such factors and discuss experimental hurdles associated with assigning intramitochondrial functions.