Abstract
Mitochondrial dysfunction is emerging as an important contributory factor to the pathophysiology of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs appears to be multifactorial, although impaired mitophagy and oxidative stress appear to be common inhibitory mechanisms shared amongst these heterogeneous disorders. Once impaired, dysfunctional mitochondria may impact upon the function of the lysosome by the generation of reactive oxygen species as well as depriving the lysosome of ATP which is required by the V-ATPase proton pump to maintain the acidity of the lumen. Given the reported evidence of mitochondrial dysfunction in LSDs together with the important symbiotic relationship between these two organelles, therapeutic strategies targeting both lysosome and mitochondrial dysfunction may be an important consideration in the treatment of LSDs. In this review we examine the putative mechanisms that may be responsible for mitochondrial dysfunction in reported LSDs which will be supplemented with morphological and clinical information.
Highlights
Lysosomal storage diseases (LSDs) consist of a group of more than 70 inherited metabolic conditions caused by defects in genes that encode proteins involved in lysosomal homeostasis including lysosomal enzymes, non-enzymatic membrane proteins or non-lysosomal proteins [1]
The removal of damaged mitochondria prevents the accumulation of reactive oxygen species (ROS) that are an inevitable consequence of impaired oxidative phosphorylation and may cause further impairment of mitochondria compromising cellular energy status [5]
In addition to morphological abnormalities, potential mitochondrial dysfunction in MPS IIIC has been indicated by the decreased mitochondrial respiratory chain (MRC) complex II and IV activities detected in brain mitochondria isolated from the MPS IIIC mouse model at the latter stages of the disease which was accompanied by a deficit in cerebral coenzyme Q10 (CoQ10) status [44,45]
Summary
Lysosomal storage diseases (LSDs) consist of a group of more than 70 inherited metabolic conditions caused by defects in genes that encode proteins involved in lysosomal homeostasis including lysosomal enzymes, non-enzymatic membrane proteins or non-lysosomal proteins [1]. The autophagic degradation of mitochondria is known as mitophagy This process enables the removal of dysfunctional mitochondria from the cell [5]. Lysosomal acidification requires functioning mitochondria to provide the requisite ATP for this process, no studies as far as the authors are aware have reported lysosomal dysfunction in patients with primary mitochondrial defects. In addition to impairing oxidative phosphorylation and depriving the V-ATPase of a source of ATP, a deficit in CoQ10 may compromise the function of the lysosomal respiratory chain that is required for maintaining the acidity of this organelle [10]. Case reports of patients with the LSDs, FD, and Pompe disease (PD) will be used to outline morphological and clinical evidence of mitochondrial dysfunction in these disorders
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