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Molecular Mechanisms of Mitochondrial Neurodegenerative Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 807

Special Issue Editors


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Guest Editor
Department of Experimental Medicine, University of Salento, Via Monteroni, 73100 Lecce, Italy
Interests: molecular biology of mitochondrial neurodegenerative disorders

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Guest Editor
Istituto di Bioscienze e BioRisorse-UOS Napoli-CNR c/o Dipartimento di Biologia, Sezione di Igiene, 80134 Naples, Italy
Interests: food; phenolic compounds; antioxidant capacity; grains; biotechnologies applied to the plant species sorghum

Special Issue Information

Dear Colleagues,

Mitochondrial diseases are a diverse group of rare genetic disorders that result from dysfunctions in the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). These defects are implicated in several neurodegenerative diseases, including Alzheimer’s and Parkinson’s, Melas, Merrf, Lhon, and Leigh Syndrome, among others. Mitochondria, the energy-producing organelles in eukaryotic cells, are regulated by two genetic systems: nuclear DNA, which encodes 90–95% of mitochondrial proteins, and mitochondrial DNA, which encodes the remaining 5%. Mitochondria also contain their own ribosomes, responsible for synthesizing key proteins essential for OXPHOS biogenesis. Diseases can arise from defects in either cytoplasmic (80S) or mitochondrial (70S) ribosomes, commonly due to haploinsufficiency or disruptions in ribosome biogenesis. This Special Issue focuses specifically on studies on mitochondrial ribosomal proteins encoded by nuclear genes, whose mutations may contribute to neurodegenerative diseases of mitochondrial origin. Identifying these proteins will enhance our understanding of the molecular mechanisms underlying mitochondrial dysfunctions and may lead to novel therapeutic approaches. These findings could contribute to the development of effective treatments and preventive strategies for mitochondrial-related neurodegeneration. We also welcome studies investigating the mechanisms of mitochondrial-related neurodegenerative diseases and other related topics.

Dr. Matteo Calcagnile
Dr. Paola Pontieri
Guest Editors

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Keywords

  • mitochondrial disease
  • nuclear genome
  • mitochondrial genome
  • human MRP genes
  • MRPL44
  • NAM9
  • GEP3
  • Alzheimer’s disease
  • Parkinson’s disease
  • yeast and C. elegans model organisms

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Published Papers (1 paper)

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Review

28 pages, 1198 KB  
Review
A Perspective on the Role of Mitochondrial Biomolecular Condensates (mtBCs) in Neurodegenerative Diseases and Evolutionary Links to Bacterial BCs
by Matteo Calcagnile, Pietro Alifano, Fabrizio Damiano, Paola Pontieri and Luigi Del Giudice
Int. J. Mol. Sci. 2025, 26(17), 8216; https://doi.org/10.3390/ijms26178216 - 24 Aug 2025
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Abstract
Biomolecular condensates (BCs), formed through liquid–liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, [...] Read more.
Biomolecular condensates (BCs), formed through liquid–liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Mitochondrial Neurodegenerative Diseases)
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