Therapy Prospects for Mitochondrial DNA Maintenance Disorders

Abstract

Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited.

Mice lacking the mitochondrial exonuclease MGME1 develop inflammatory kidney disease with glomerular dysfunction

“…The mtDNA maintenance diseases are genetically and clinically heterogenous with severities ranging from infantile fatal forms to adult onset of mild disease. Whereas organs with high energy demands, such as heart, skeletal muscle and the central nervous system, often are affected, manifestations can occur in many different organs [ 19 ]. Kidneys contain a high density of mitochondria, particularly in the cortical tubules, but all sections of the nephron may be affected by mitochondrial dysfunction.…”

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

“…As mitochondria replicate independently from the cell cycle and distribute randomly to the daughter cells after mitosis, the degree of heteroplasmy can widely differ within a given tissue [39]. If a certain heteroplasmy threshold is exceeded, mitochondrial homeostasis can be impaired, subsequently leading to impairments similar to those seen in primary mitochondrial disease and ultimately to cell death [40] (see Figure 2). There is strong experimental evidence that genetic variations in mtDNA increase with age, which also translates to our pathophysiological understanding of the development of neurodegenerative diseases [41].…”

“…While it is not entirely understood how mtDNA deletions occur, several hypotheses were suggested: In most cases, mtDNA deletions occur randomly and appear to undergo clonal expansion. Another theory suggests that critical pathways for mtDNA replication and quality control are impaired in neurodegenerative disorders [40]. The maintenance of mtDNA requires a variety of nDNA-encoded gene products.…”

Molecular Research on Mitochondrial Dysfunction

“…They review how heteroplasmy might evolve towards a predominant wild-type or mutated genotype in the cell, reporting mtDNA mutations that prevail in specific tumors with respect to the non-tumoral tissue, and suggest a positive contribution to the proliferation and survival of neoplastic cells [ 4 ] ( Figure 1 ). Furthermore, Ramòn and colleagues discuss the processes and proteins governing mtDNA copy number and stability, in which dysregulation triggers the onset of mtDNA depletion and deletion syndromes [ 5 ].…”

“…Despite the many difficulties in developing therapies for mitochondrial diseases, some important milestones have been reached, as discussed by Ramòn and colleagues [ 5 ]. These authors focused on mtDNA maintenance defects; these are a highly relevant group of mitochondrial diseases resulting from mutations in genes that encode components of the replication/transcription machinery, of nucleotide metabolism, and of mitochondrial dynamics.…”