# New Insights on Mitochondria-Targeted Neurological Drugs

## TL;DR

This paper explores how targeting mitochondria with specific drugs can help treat neurological diseases and aging-related issues by improving mitochondrial function.

## Contribution

The paper provides new insights into the mechanisms and therapeutic potential of mitochondria-targeted drugs for neurological disorders.

## Key findings

- Mitochondria-targeted drugs like Mito-Q and Mito-apocynin show promise in restoring mitochondrial respiratory chain function.
- Elamipretide and SkQ1 stabilize cardiolipin, offering a therapeutic approach to prevent bioenergetic impairment.
- Modulating calcium signaling and mitophagy pathways presents new strategies for treating neurodegenerative diseases.

## Abstract

Mitochondria play a central role in energy production, free radical formation and calcium homeostasis, as well as in the modulation of neuronal cell death and survival. In the nervous system, neurons rely almost exclusively on ATP synthesis from the mitochondrial respiratory chain and oxidative phosphorylation to fulfill their energy requirements for neurotransmitter synthesis, release and reuptake. Within the nerve terminals, mitochondria are essential to maintain an adequate synaptic function. Mitochondrial dysfunction is involved in physiological aging and in many neurological diseases. Mitochondria-targeted drugs are based on their lipophilic moieties, the possibility of binding to mitochondrial membrane lipids and/or their ability to act as antioxidants or uncouplers. Possible sites of pharmacological intervention that represent mitochondrial targets are mitochondrial electron transport chain and oxidative phosphorylation, cardiolipin, active oxygen species generation, calcium signaling, mitochondrial biogenesis and dynamics and mitophagic pathways. Insights on the potential therapeutic benefits of mitochondrial-targeted drugs are presented herein in terms of the described effects in animal models and clinical studies. The evaluation of mitochondria as a promising target for development of new therapeutic strategies is discussed, with the aim of preventing mitochondrial dysfunction associated with aging damage and neurodegenerative disorders.

Aging and neurodegenerative diseases are characterized by common features involving bioenergetics deficiencies, oxidative stress and alterations of calcium buffering. Mechanisms of mitochondrial-targeted drugs include the modulation of electron transport chain and oxidative phosphorylation, the binding to mitochondrial lipids, free-radical scavenging, calcium signaling, and possible effects on mitochondrial biogenesis and dynamics and on the regulation of mitophagic pathways. One of the main sites of action of mitochondria-targeted drugs is the interaction with respiratory chain components. Mitochondrial-targeted compounds such as Mito-Q, and Mito-apocynin have been developed by conjugating triphenylphosphonium (TPP+) lipophilic cation group with natural molecules, therefore obtaining promising drugs for reestablishing the correct functioning of the mitochondrial respiratory chain. Stabilization of cardiolipin at the inner mitochondrial membrane by elamipretide or SkQ1 and mitochondria-targeted ROS scavengers can also offer a therapeutic approach to prevent bioenergetic impairment associated with several diseases. In addition, the modulation of calcium signaling can be achieved using both MCU agonists and antagonists representing another mitochondrial target for drug therapies development. Finally, potential strategies for treating neurodegenerative diseases based on the modulation of mitochondrial biogenesis, dynamics and/or mitophagic pathways are discussed.