Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies
12 affiliations
- 1Physiology 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
- 2Anatomy 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
- 3Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates
- 4Department of Pathology, Faculty of Medicine, MAHSA University, Bandar Saujana Putra, Jenjarom 42610, Selangor, Malaysia
- 5Faculty of Medicine, Nursing and Health Sciences, SEGi University, 9, Jalan Teknologi, Pju 5 Kota Damansara, Petaling Jaya 47810, Selangor, Malaysia
- 6Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Jln Datuk Mohammad Musa, Kota Samarahan 94300, Sarawak, Malaysia
- 7School of Medicine, IMU University, 126, Jln Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia
- 8Department of Anatomy, School of Medicine, Taylor’s University, Lakeside Campus, 1, Jln Taylors, Subang Jaya 47500, Selangor, Malaysia
- 9Clinical Skills Suite, School of Medicine, Taylor’s University, Lakeside Campus, 1, Jln Taylors, Subang Jaya 47500, Selangor, Malaysia
- 10Department of Basic Medical Sciences, Faculty of Medicine, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya 63000, Selangor, Malaysia
- 11Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia
- 12Department 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
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.
Related
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BibTeX
@article{gopalakrishna2026mitochondrial,
title = {{Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies}},
author = {Prarthana Kalerammana Gopalakrishna and Thirupathirao Vishnumukkala and Zaw Myo Hein and Barani Karikalan and Srikumar Chakravarthi and Farida Hussan and Riya Sandeep Deoghare and Saravanan Jagadeesan and Narendiran Krishnasamy and Soe Ei Phyu and Pamela David and Mohd Amir Kamaruzzaman},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219993},
url = {https://www.mdpi.com/1422-0067/27/21/9993},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies
AU - Prarthana Kalerammana Gopalakrishna
AU - Thirupathirao Vishnumukkala
AU - Zaw Myo Hein
AU - Barani Karikalan
AU - Srikumar Chakravarthi
AU - Farida Hussan
AU - Riya Sandeep Deoghare
AU - Saravanan Jagadeesan
AU - Narendiran Krishnasamy
AU - Soe Ei Phyu
AU - Pamela David
AU - Mohd Amir Kamaruzzaman
PY - 2026
DA - 2026/11/07
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219993
UR - https://www.mdpi.com/1422-0067/27/21/9993
AB - 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.
SN - 1422-0067
ER -