{
  "abstract": "Mitochondria are critical for bioenergetics, calcium and redox homeostasis, and apoptosis in neurons. Neurons are especially susceptible to mitochondrial malfunction since they are terminally differentiated and have extraordinary energy requirements. Mechanisms such as defective oxidative phosphorylation, altered fission-fusion dynamics, defective mitophagy, impaired axonal transport and excessive reactive oxygen species (ROS) generation are increasingly appreciated as important mechanisms in major neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). The review discusses the structure and function of mitochondria with emphasis on oxidative phosphorylation, ROS and reactive nitrogen species (RNS) signalling, calcium-mediated excitotoxicity, lipid metabolism, and apoptotic and non-apoptotic cell-death mechanisms including necroptosis, ferroptosis, pyroptosis and parthanatos. In particular, disease-specific processes are highlighted, such as impaired mitophagy by amyloid β/tau in AD, PTEN-induced kinase 1 (PINK1)/Parkin dysfunction and complex I inhibition in PD, Superoxide Dismutase 1 (SOD1)/C9orf72-associated mitochondrial defects in ALS, and bioenergetic dysfunction by mutant huntingtin in HD. Therapeutic approaches include mitochondria-targeted antioxidants, fusion and biogenesis enhancers, fission inhibitors, inflammasome modulators, Mitochondrial Permeability Transition Pore (mPTP) inhibitors and gene therapy. Also highlighted are recent advancements such as Ubiquitin-Specific Peptidase 30 (USP30) inhibition, intercellular mitochondrial transfer and regulatory approval of a mitochondria-targeted peptide, together with evidence supporting causality and hurdles underpinning clinical translation. Graded against human-genetic, patient-tissue and model-based evidence, mitochondrial dysfunction is best supported as a primary driver in PD and genetic ALS, and as an early amplifier of proteinopathic or mutant-huntingtin toxicity in sporadic AD and HD.",
  "abstract_shown": true,
  "affiliations": [
    "Physiology Discipline, Human Biology Division, School of Medicine, IMU University, 126, Jln Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia",
    "Anatomy Discipline, Human Biology Division, School of Medicine, IMU University, 126, Jln Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia",
    "Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates",
    "Department of Pathology, Faculty of Medicine, MAHSA University, Bandar Saujana Putra, Jenjarom 42610, Selangor, Malaysia",
    "Faculty of Medicine, Nursing and Health Sciences, SEGi University, 9, Jalan Teknologi, Pju 5 Kota Damansara, Petaling Jaya 47810, Selangor, Malaysia",
    "Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Jln Datuk Mohammad Musa, Kota Samarahan 94300, Sarawak, Malaysia",
    "School of Medicine, IMU University, 126, Jln Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia",
    "Department of Anatomy, School of Medicine, Taylor’s University, Lakeside Campus, 1, Jln Taylors, Subang Jaya 47500, Selangor, Malaysia",
    "Clinical Skills Suite, School of Medicine, Taylor’s University, Lakeside Campus, 1, Jln Taylors, Subang Jaya 47500, Selangor, Malaysia",
    "Department of Basic Medical Sciences, Faculty of Medicine, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya 63000, Selangor, Malaysia",
    "Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia",
    "Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Prarthana Kalerammana Gopalakrishna"
    },
    {
      "affs": [
        1
      ],
      "name": "Thirupathirao Vishnumukkala"
    },
    {
      "affs": [
        2
      ],
      "name": "Zaw Myo Hein",
      "orcid": "0000-0001-7621-7132"
    },
    {
      "affs": [
        3
      ],
      "name": "Barani Karikalan"
    },
    {
      "affs": [
        4
      ],
      "name": "Srikumar Chakravarthi",
      "orcid": "0000-0002-9888-3301"
    },
    {
      "affs": [
        5
      ],
      "name": "Farida Hussan",
      "orcid": "0000-0002-0197-4646"
    },
    {
      "affs": [
        6
      ],
      "name": "Riya Sandeep Deoghare"
    },
    {
      "affs": [
        7
      ],
      "name": "Saravanan Jagadeesan"
    },
    {
      "affs": [
        8
      ],
      "name": "Narendiran Krishnasamy"
    },
    {
      "affs": [
        9
      ],
      "name": "Soe Ei Phyu"
    },
    {
      "affs": [
        10
      ],
      "name": "Pamela David",
      "orcid": "0000-0003-2724-6249"
    },
    {
      "affs": [
        11
      ],
      "name": "Mohd Amir Kamaruzzaman",
      "orcid": "0000-0003-4163-2234"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9ra2nwpphk687.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219993",
  "fulltext_url": null,
  "id": "9ra2nwpphk687",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9993",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-07",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/9ra2nwpphk687.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T00:21:27Z",
      "native_id": "10.3390/ijms27219993",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9993"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "issn:1422-0067",
      "subfield": "general"
    }
  ],
  "title": "Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies",
  "title_text": "Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T00:21:27Z",
  "url": "https://research.draconitic.com/paper/9ra2nwpphk687",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}