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Among all the organelles in an animal cell, only mitochondria have their own independent genomes. Animal mitochondrial DNA is a double-stranded, closed-circular molecule with around 20,000 base pairs. Mitochondrial DNA is unique in that one of its two strands, the heavy, or H, -strand is guanine rich, whereas the complementary strand is cytosine rich and called the light, or L, -strand. Compared to nuclear DNA, mitochondrial DNA has a very low percentage of non-coding regions and is marked by...
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Mitochondria are eukaryotic cellular organelles that are known to produce energy through a process called oxidative phosphorylation. Besides their primary function, mitochondria are involved in various cellular processes, including cell growth, differentiation, signaling, metabolism, and senescence. Age-related changes cause a decline in mitochondrial quality and integrity due to increased mitochondrial mutations and oxidative damage. Thus, aging can severely impact mitochondrial functions,...
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A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
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A eukaryotic cell can have up to three different types of genetic systems: nuclear, mitochondrial, and chloroplast. During evolution, organelles have exported many genes to the nucleus; this transfer is still ongoing in some plant species. Approximately 18% of the Arabidopsis thaliana nuclear genome is thought to be derived from the chloroplast’s cyanobacterial ancestor, and around 75% of the yeast genome derived from the mitochondria’s bacterial ancestor. This export has occurred...
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The inner mitochondrial membrane is the primary site of ATP synthesis. The inner membrane domain that forms a smooth layer adjacent to the outer membrane is called the inner boundary membrane. This domain contains membrane transporters that drive metabolites in and out of the mitochondria.  In contrast, the inner membrane network that invaginates into the matrix space is called the cristae membrane. This domain accounts for principle mitochondrial function as it accommodates the protein...
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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
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Consequences of compromised mitochondrial genome integrity.

Margaret A Gustafson1, Eric D Sullivan1, William C Copeland1

  • 1Mitochondrial DNA Replication Group, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC, 27709, USA.

DNA Repair
|October 22, 2020
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Summary

Mitochondrial DNA (mtDNA) replication is vital for energy production. Mutations in core mtDNA replisome genes cause mtDNA damage, leading to dysfunctional mitochondria and diverse diseases.

Keywords:
Mitochondrial DNAMitochondrial diseaseMutagenesisPOLGPOLG2ReplicationSSBP1TWNK

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Mitochondrial DNA (mtDNA) maintenance and replication are crucial for mitochondrial function and cellular energy production via the electron transport chain.
  • The mitochondrial replisome, comprising Pol γ, Twinkle, and single-stranded DNA binding protein, is essential for mtDNA replication.
  • Mitochondrial DNA is vulnerable to damage from both internal and external factors, with limited repair pathways compared to nuclear DNA.

Purpose of the Study:

  • To review the mechanisms underlying mitochondrial DNA damage.
  • To discuss the clinical consequences of disease-causing variants in the core mtDNA replisome genes.

Main Methods:

  • Review of existing literature on mtDNA replication, damage, and repair mechanisms.
  • Analysis of the impact of missense mutations in nuclear genes encoding core mtDNA replisome proteins (POLG, POLG2, TWNK, SSBP1).

Main Results:

  • Mutations in POLG, POLG2, TWNK, and SSBP1 alter the biochemical functions of their protein products.
  • These altered protein variants can lead to mtDNA damage and disrupt oxidative phosphorylation.
  • Accumulated mtDNA damage contributes to mitochondrial dysfunction.

Conclusions:

  • Variants in core mtDNA replisome genes result in significant mtDNA damage and cellular dysfunction.
  • This damage underlies a wide spectrum of diseases affecting multiple organ systems.
  • Understanding these mechanisms is key to addressing mitochondrial diseases.