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Related Concept Videos

Animal Mitochondrial Genetics02:59

Animal Mitochondrial Genetics

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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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Gene Therapy00:59

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Gene therapy is a technique where a gene is inserted into a person’s cells to prevent or treat a serious disease. The added gene may be a healthy version of the gene that is mutated in the patient, or it could be a different gene that inactivates or compensates for the patient’s disease-causing gene. For example, in patients with severe combined immunodeficiency (SCID) due to a mutation in the gene for the enzyme adenosine deaminase, a functioning version of the gene can be...
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Electron Transport Chain: Complex I and II01:46

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The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
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ATP Synthase: Mechanism01:48

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In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
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Energy to Drive Translocation01:37

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Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
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Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death.  Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
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An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
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Gene therapy for mitochondrial disorders.

Nandaki Keshavan1,2, Michal Minczuk3, Carlo Viscomi4,5

  • 1UCL Great Ormond Street Institute of Child Health, London, UK.

Journal of Inherited Metabolic Disease
|January 3, 2024
PubMed
Summary
This summary is machine-generated.

Gene therapy shows promise for primary mitochondrial disorders (PMDs) using adeno-associated virus vectors and gene editing tools. Clinical trials for Leber Hereditary Optic Neuropathy are advancing, but challenges in organ targeting and trial design remain.

Keywords:
AAVCRISPRLHONgene editinggene therapymitochondrial disease

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Area of Science:

  • Genetics
  • Molecular Biology
  • Neurology

Background:

  • Primary mitochondrial disorders (PMDs) are a heterogeneous group of debilitating genetic diseases.
  • Current treatments for PMDs are limited, highlighting the need for novel therapeutic strategies.
  • Gene therapy offers a promising avenue for addressing the underlying genetic defects in PMDs.

Purpose of the Study:

  • To review the current applications of gene therapy in treating primary mitochondrial disorders.
  • To highlight advancements in gene replacement and gene editing technologies for PMDs.
  • To discuss the challenges and future directions for clinical translation of gene therapy for PMDs.

Main Methods:

  • Review of preclinical studies using recombinant adeno-associated virus (rAAV) vectors for gene replacement in PMD mouse models.
  • Analysis of clinical trial data for lenadogene nolparvovec in Leber Hereditary Optic Neuropathy.
  • Evaluation of gene editing technologies, including nucleases (TALENs, ZFNs, mitoARCUS) and CRISPR-Cas9, for targeting nuclear and mitochondrial DNA defects.
  • Assessment of in vivo delivery methods for gene therapy and gene editing tools.

Main Results:

  • Successful preclinical gene replacement in over ten PMD mouse models using advanced rAAV technologies for organ targeting.
  • Positive outcomes in Phase 3 clinical trials of lenadogene nolparvovec for Leber Hereditary Optic Neuropathy, demonstrating efficacy and tolerability.
  • Advancements in nucleases and CRISPR-based gene editing show potential for treating both nuclear and mitochondrial DNA defects in PMDs.
  • In vivo delivery of gene editing tools via rAAV has been successful in mouse models.

Conclusions:

  • Gene therapy, particularly using rAAV vectors and gene editing, holds significant therapeutic potential for primary mitochondrial disorders.
  • Leber Hereditary Optic Neuropathy is a leading example of successful gene therapy translation, with ongoing clinical trials.
  • Overcoming challenges in organ transduction efficiency and optimizing clinical trial design are crucial for broader application of gene therapy in PMDs.