TABLE 5.
Overview of preclinical and clinical efforts targeting mitochondrial biology (as covered in this review). BCL-2 (B-cell lymphoma 2), DRP1 (dynamin-related protein 1), ER (endoplasmic reticulum), ERK (extracellular signal-regulated kinase), ETBR (endothelin B receptor), GSK3β (glycogen synthase kinase-3 beta), HMGB1 (high-mobility group box 1), HD (Huntington’s disease), IAPs (inhibitor of apoptosis proteins), MCU (mitochondrial calcium uniporter), S6K1(p70 S6 ribosomal kinase).
| Process | Indication | Compound/Drug | Mechanism of action | Citation |
|---|---|---|---|---|
| Mitochondrial morphology | Hypoxic-ischemic encephalopathy | Sovateltide (PMZ-1620; IRL-1620) | Agonism of ETBR to promote higher differentiation of neuronal progenitor cells with improved mitochondrial morphology | NCT05514340 |
| Alzheimer’s disease | PD98058, mdivi-1, probucol | Inhibition of ERK to restores mitochondrial fusion/fission balance | Gan et al. (2014) | |
| Pulmonary hypertension | Trimetazidine | Inhibition of fatty acid oxidation to improve mitochondrial fusion/fission balance | NCT02102672 | |
| Myocardial ischemia reperfusion injury | Astragaloside IV derivative (LS-102) | Inhibition of GSK3β-mediated DRP1 phosphorylation at S616 to reduce mitochondrial fragmentation | Chen et al. (2020) | |
| Cellular apoptosis | Solid malignancies (patients did not respond to standard treatemnts) | Debio 1142 in combination with Nivolumab | Antagonism of IAPs to induce apoptosis in combination with immune checkpoint inhibition | NCT04122625 |
| Relapsed or refractory advanced malignant tumours | TQB3909 | Inhibition of BCL-2 to induce apoptosis | NCT04975204 | |
| Glioblastoma | Piticlisib (GDC-0941) in combination with ABT-263 | PI3K inhibition to inhibit BAD phosphorylation at S112 and 136 sensitising to BCL-2 inhibition | Pareja et al. (2014) | |
| Peritoneal carcinomatosis | Mitomycin C in combination with rapamycin | Chemotherapy with mTOR inhibition to induce apoptosis by BAD dephosphorylation via inactivation of S6K1 | Song et al. (2014) | |
| Brain damage after ischemia-reperfusion | Dexmedetomidine | Decrease in ER stress-induced neuronal apoptosis | Zhai et al. (2019) | |
| Neuronal injury during brain surgery | Dexmedetomidine | Minimised neuronal injury by reducing apoptosis | NCT02878707 | |
| Ca2+ homeostasis and MAMs regulation | Huntington’s disease | Pridopidine (ACR16) | Agonism of Sig-1R to show promise in improving HD motor phenotypes | NCT00665223, de Yebenes et al. (2011) |
| Amyotrophic lateral sclerosis | Pridopidine (ACR16) | Agonism of Sig-1R to improve speech measures | NCT04615923 | |
| Parkinson’s disease | Ruthenium red | MCU inhibition to rescue dopaminergic neurons in pink1 deficient zebrafish | Soman et al. (2017) | |
| ROS signalling | Graft-versus host disease | MIT-001 | ROS scavenging to decrease HMGB1 expression and oxidative stress | Im et al. (2015) |
| Head and neck squamous cell carcinoma patients undergoing chemoradiotherapy | MIT-001 | ROS scavenging to prevent chemoradiotherapy-associated oral mucositis (caused by high ROS and excessive inflammation) | NCT04651634 | |
| Heart failure | Nicotinamide riboside | Increase in NAD+ levels to improve mitochondrial and thus cardiac function | NCT04528004 | |
| Breast cancer patients undergoing treatment with doxorubicin-adjuvant chemotherapy | Mitoquinone | Prevention of doxorubicin-induced oxidative stress | NCT05146843 |