Putative adjunct therapies to target mitochondrial dysfunction and oxidative stress in phenylketonuria, lysosomal storage disorders and peroxisomal disorders

ABSTRACT

Introduction: Oxidative stress (OS) and mitochondrial dysfunction are implicated in the pathogenesis of a number of metabolic diseases. OS occurs when there is an imbalance between the pro-oxidant/antioxidant homeostasis, leading to an increased generation of reactive oxidant species (ROS) with resultant cellular dysfunction. It is becoming apparent that increased ROS generation may be attributable to secondary mitochondrial dysfunction as a  consequence of disease pathophysiology. Mitochondrial dysfunction occurs as a result of oxidative damage from enhanced ROS generation as well as the accumulation of toxic metabolites in some metabolic diseases.

Areas covered: The present review will discuss evidence of OS and mitochondrial dysfunction in phenylketonuria (PKU), lysosomal storage disorders (LSDs), and peroxisomal disorders. In addition, potential adjunct therapies which have the potential to enhance mitochondrial functioning and mitigate OS will be explored. The databases utilized for this review were Pubmed and the Wed of science, with inclusive dates, 1988–2020.

Expert opinion: There is an un-unified approach in the treatment of metabolic diseases. Agents including augmenters of mitochondrial function, antioxidants, and activators of mitochondrial biogenesis, may be beneficial. However, although successful in some cases, these adjunct therapies have yet to be incorporated into the clinical-management of metabolic diseases.

KEYWORDS:

• Metabolic disease
• phenylketonuria
• lysosome storage disorders
• peroxisome disorders
• mitochondrial biogenesis
• mitochondrial electron transport chain
• oxidative stress
• antioxidants

Article highlights

• The metabolic diseases PKU, LSDs, and peroxisome disorders have all demonstrated evidence of mitochondrial dysfunction and oxidative stress as part of their disease pathophysiology.

• Certain adjunct therapies have shown to be beneficial in augmenting ETC function and mitigating OS in primary ETC disorders and other diseases associated with similar disease pathophysiology.

• There is still a severe paucity of research of these treatments in IEM, however, they primarily focus on their ability to enhance mitochondrial ETC functioning and mitigating mitochondrial OS.

• Agents, which stimulate mitochondrial biogenesis, an integral event, which sustains mitochondrial oxidative phosphorylation is gaining more attention in recent years as therapies move from cell-based studies into clinical trials for their ability to improve mitochondrial ETC functioning.

• The therapies discussed are potential adjunct therapies to be taken in conjunction with IEM recommended dietary intervention and primary disease treatments.

• At present, it is difficult to decipher how the treatment of mitochondrial dysfunction and OS in IEM will evolve. A lot of research is still required to evaluate the therapeutic efficacy of these agents in IEM. However, until biomarkers of mitochondrial dysfunction in IEM patients become more reliable, the therapeutic efficacy of these agents will be difficult to quantify.

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Declaration of interest

N Turton has received a PhD research grant funded by Vitaflo Ltd UK. T Rutherford is the lead researcher at Vitaflo Ltd. 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. 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded.