Topic: Mitochondrial Disorders: Molecular Mechanisms, Biomarkers, and Therapeutic Horizons

Mitochondrial disorders represent a heterogeneous group of complex genetic conditions caused by pathogenic variants in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins. Traditionally, clinical management has focused primarily on symptomatic relief rather than disease modification. However, recent breakthroughs in gene-editing technologies—including clustered regularly interspaced short palindromic repeats (CRISPR)-based systems, transcription activator-like effector nucleases (TALENs), and novel mtDNA-specific editors—have unlocked transformative potential for correcting pathogenic mutations at their molecular origin. This Special Issue of Rare Disease and Orphan Drugs Journal seeks to highlight cutting-edge advances in the mechanistic understanding, diagnosis, and treatment of mitochondrial disorders, with a particular emphasis on emerging therapeutic strategies, notably gene editing and precision medicine approaches. We invite submissions of Original Research Articles, Reviews, Case Reports, Perspectives, and Brief Communications addressing the following thematic areas:

1. Disease Mechanisms and Biomarkers: Novel insights into mitochondrial pathophysiology, heteroplasmy dynamics, and the identification of diagnostic or prognostic biomarkers with clinical utility.

2. Gene Editing and Precision Therapies:

    - Development and optimization of mtDNA-specific gene-editing tools;

    - Innovative delivery systems enabling targeted mitochondrial cargo transport;

    - Preclinical validation studies using cellular, organoid, or in vivo animal models;

    - Strategies to enhance editing efficiency, modulate heteroplasmy thresholds, and mitigate off-target effects;

    - Ethical, regulatory, and safety considerations related to the clinical translation of mitochondrial gene-editing therapies.

3. Orphan Drug Development: Preclinical and clinical investigations of small-molecule therapeutics, enzyme replacement therapies, metabolic supplements, and drug repurposing strategies for mitochondrial disorders.

4. Clinical Management and Multidisciplinary Care: Evidence-based diagnostic guidelines, long-term monitoring protocols, palliative care approaches, and standardized multidisciplinary care pathways.

5. Policy, Access, and Patient Advocacy: Health economic analyses, orphan drug designation pathways, reimbursement policy frameworks, and initiatives aimed at advancing global equity in access to care.

6. Patient-Centered Research: Quality-of-life assessments, investigations into psychosocial impacts, and community-engaged research initiatives conducted in partnership with patient stakeholders.