Life science
Life science, Cell biology

Improving mitochondrial function
by controlling mitochondrial DNA movement
Department of Biological Sciences, Graduate School of Science
Professor Naotada Ishihara
https://researchmap.jp/10325516?lang=en

Life science

Abstract
We have shown that a molecule known as ATAD3A is essential
for the movement of genetic material inside intracellular substructures called mitochondria. Appropriate distribution of mitochondrial
DNA (mtDNA), organized into “nucleoid” structures, is key for thegeneration of energy by the “respiratory chain” protein complex.
This study opens up opportunities for developing new methods toalter nucleoid movement and affect mitochondrial function, thereby
providing potential therapies against mitochondrial diseases.

▍ Background & Results
Mitochondria, famously known as the powerhouse of the cell, areimportant cellular structures that are vital for their role of generatingenergy. Mitochondria are “dynamic”, meaning they constantly fuse
together and split apart. They contain a small amount of genetic
information known as mitochondrial DNA (mtDNA). The mtDNA,
organized into dot-like structures called “nucleoids”, also moves
around inside the mitochondria. We had previously shown that themovement of the nucleoids is linked to the fission of mitochondria.
However, the mechanisms and function of this movement were unclear.
Here we have identified a molecule known as ATAD3A that is essential for nucleoid movement and could be a potential therapeuticcandidate for mitochondrial diseases. ATAD3A, which is anchoredFig for English

to the inner mitochondrial membrane, mediated the interaction ofmtDNA nucleoids (present inside the mitochondria) with factors involved in mitochondrial fission (present on the outer mitochondrialmembrane). They demonstrated that ATAD3A was essential for theactive movement of mtDNA nucleoids within the mitochondria—aprocess called nucleoid “trafficking”—and that nucleoids were abnormally clustered in cells that lack mitochondrial fission. Together,mitochondrial fission and nucleoid trafficking determine the size,
number, and distribution of the nucleoids within the mitochondria,
and that regulation of nucleoid dynamics is crucial for the maintenance of respiratory chain complexes on the mitochondrial inner
membrane.

▍ Significance of the research and Future perspective
The distribution of nucleoids throughout the mitochondrial network activates expression of the mtDNA and increases formationof the “respiratory chain complex”, which is a group of several
protein complexes essential for energy production within cells, andthe correct distribution of the mtDNA nucleoids is key for efficientenergy production. The development of techniques to alter mtDNA
movement may help regulate mitochondrial function in the future.
Therefore, not only does this work increase our knowledge of theregulatory processes in mitochondria but it also provides scope fordeveloping future therapies against abnormal mitochondrial functioning.

HeLa cell

mitochondrial DNA

mitochondrial DNAmitochondria

Defect on mtDNA trafficking

Defect on mitochondrial fission

Drp1 deficiency

ATAD3 deficiency

mtDNA

ATAD3A

Dispersed mtDNA nucleoids→ enhance OXPHOS

mtDNA

ATAD3A

Clustered mtDNA nucleoids→ desreased OXPHOSP a t e n t
Ishihara, Takaya et al. Mitochondrial nucleoid trafficking regulated by the inner-membrane AAA-ATPase ATAD3A modulates respiratory complex formation.
Proceedings of the National Academy of Science of the United States of America. 2022, 119 (47): e2210730119. doi: 10.1073/pnas.2210730119
UR
L https://mitochondria.jp/englishpageK e y w o r d cellular energetics, mitochondrial diseases, mitochondrial DNA, mitochondrial fission, respiratory proteinsTr e a t i s e