Targeting autophagy and mitophagy for mitochondrial diseases treatment

Abstract

Introduction: Mitochondrial diseases are a group of rare genetic diseases with complex and heterogeneous origins which manifest a great variety of phenotypes. Disruption of the oxidative phosphorylation system is the main cause of pathogenicity in mitochondrial diseases since it causes accumulation of reactive oxygen species (ROS) and ATP depletion.

Areas covered: Current evidences support the main protective role of autophagy and mitophagy in mitochondrial diseases and other diseases associated with mitochondrial dysfunction.

Expert Opinion: The use of autophagy and/or mitophagy inducers may allow a novel strategy for improving mitochondrial function for both mitochondrial diseases and other diseases with altered mitochondrial metabolism. However, a deeper investigation of the molecular mechanisms behind mitophagy and mitochondrial biogenesis is needed in order to safely modulate these processes. In the coming years, we will also see an increase in awareness of mitochondrial dynamics modulation that will allow the therapeutic use of new drugs for improving mitochondrial function in a great variety of mitochondrial disorders.

Keywords:

• AICAR
• AMPK
• autophagy
• coenzyme Q₁₀
• heteroplasmy
• mitochondrial dynamics
• mitophagy
• mTOR
• Parkin
• rapamycin
• ROS

6. Article highlights.

• Accumulation of dysfunctional mitochondria is one of the main causes of worsening of the pathophysiology in mitochondrial diseases.

• Autophagy and mitophagy seem to play a protective role in mitochondrial diseases.

• Disruption of autophagy and/or mitophagy is a characteristic of many diseases with mitochondrial dysfunction (e.g., neurological diseases).

• Promotion of nonselective autophagy and/or mitophagy by pharmacological approaches could be a promising therapeutic target for mitochondrial diseases because it permits the elimination of dysfunctional mitochondria.

• Mitophagy regulation could be a curative therapy for mitochondrial diseases caused by mtDNA mutations, because we could modulate the heteroplasmy load.

• Specific removal of dysfunctional mitochondria should be accompanied by an increase in mitochondrial biogenesis to prevent the energetic collapse of the cell.This box summarizes key points contained in the article.

This box summarizes key points contained in the article.

Declaration of interest

This work was supported by FIS PI13/00129 grant, Ministerio de Sanidad, Spain, and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, and by AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de Enfermedades Neurodegenerativas por Acumulación Cerebral de Hierro). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.