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TFAM knockdown-triggered mtDNA-nucleoid aggregation and a decrease in mtDNA copy number induce the reorganization of
Koit Aasumets1, Yuliya Basikhina2, Jaakko L Pohjoismäki3
1Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia.
Biochemistry and Biophysics Reports
|October 8, 2021
Summary
Mitochondrial DNA (mtDNA) organization is crucial for genome distribution. TFAM knockdown disrupts mtDNA nucleoids, impacting ER-mitochondria contacts and triggering compensatory mechanisms.
Area of Science:
- Cell Biology
- Genetics
- Molecular Biology
Background:
- Proper mitochondrial DNA (mtDNA) organization within nucleoids and the integrity of mitochondria-ER contacts are vital for cellular genome stability.
- Mitochondria-associated ER membranes (MAMs) are critical platforms linking mitochondrial genome replication and division machinery.
Purpose of the Study:
- To investigate the impact of TFAM (mitochondrial transcription factor A) on mtDNA nucleoid organization and its subsequent effects on ER-mitochondria contacts.
- To elucidate the role of TWNK (Twinkle) helicase in mtDNA maintenance and its relationship with TFAM and MAMs.
Main Methods:
- TFAM and TWNK were knocked down using specific experimental approaches.
- Changes in mtDNA copy number, nucleoid aggregation, and MAM protein levels were analyzed.
- Mitochondrial nucleoid populations and their association with membranes were examined.
Main Results:
- TFAM knockdown led to decreased mtDNA copy number, mtDNA nucleoid aggregation, and upregulation of TWNK in membrane-associated fractions.
- These changes in TFAM-depleted cells were accompanied by transient elevation of MAM proteins, suggesting a reorganization of ER-mitochondria linkages.
- TWNK knockdown reduced mtDNA copy number and altered membrane association but did not induce nucleoid aggregation or significant MAM alterations.
Conclusions:
- mtDNA nucleoid aggregation, induced by TFAM depletion, triggers a compensatory response involving the reorganization of both nucleoids and MAMs.
- These findings offer insights into pathological conditions characterized by impaired mtDNA organization or distribution defects.
- The study highlights the intricate interplay between mtDNA nucleoids, TFAM, TWNK, and MAMs in maintaining mitochondrial and cellular homeostasis.
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