Emerging therapeutic approaches to mitochondrial diseases

Wenz, Tina; Williams, Steve K.; Bacman, Sandra R.; Moraes, Carlos T.

doi:10.1002/ddrr.109

Cited by 37 publications

(23 citation statements)

References 128 publications

(135 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a heteroplasmic state, there is a threshold effect, which ranges from 60 to 90% of mutated mtDNA depending on the tissue and mutation, resulting in OXPHOS defect, insufficient ATP levels and a diseased phenotype [238, 239]. In fact, one of the prevalent therapeutic strategies involves shifting herero-plasmy toward wild type mtDNA via increased mitochondrial biogenesis and/or turnover of mutated mitochondria to attenuate the OXPHOS deficit and therefore somatic manifestations in patients [240, 241]. …”

Section: Compensatory Mitochondrial Biogenesis Associated With Spementioning

confidence: 99%

“…This shift in heteroplasmy would optimize OXPHOS functions and alleviate symptomatic manifestations of these diseases [240, 278]. In support of this strategy are studies demonstrating that induction of mitochondrial biogenesis via transgenic overexpression of PGC-1α using a genetic approach was able to rescue ATP levels in cybrid cell lines harboring nuclear or mitochondrial mutations derived from patients with oxidative phosphorylation defects [279, 280].…”

Section: Putative Therapeutic Options To Modulate Neuronal Mitochomentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

Uittenbogaard¹,

Chiaramello

2014

CPD

197

128

View full text Add to dashboard Cite

In the developing and mature brain, mitochondria act as central hubs for distinct but interwined pathways, necessary for neural development, survival, activity, connectivity and plasticity. In neurons, mitochondria assume diverse functions, such as energy production in the form of ATP, calcium buffering and generation of reactive oxygen species. Mitochondrial dysfunction contributes to a range of neurodevelopmental and neurodegenerative diseases, making mitochondria a potential target for pharmacological-based therapies. Pathogenesis associated with these diseases is accompanied by an increase in mitochondrial mass, a quantitative increase to overcome a qualitative deficiency due to mutated mitochondrial proteins that are either nuclear- or mitochondrial-encoded. This compensatory biological response is maladaptive, as it fails to sufficiently augment the bioenergetically functional mitochondrial mass and correct for the ATP deficit. Since regulation of neuronal mitochondrial biogenesis has been scantily investigated, our current understanding on the network of transcriptional regulators, co-activators and signaling regulators mainly derives from other cellular systems. The purpose of this review is to present the current state of our knowledge and understanding of the transcriptional and signaling cascades controlling neuronal mitochondrial biogenesis and the various therapeutic approaches to enhance the functional mitochondrial mass in the context of neurodevelopmental disorders and adult-onset neurodegenerative diseases.

show abstract

Section: Compensatory Mitochondrial Biogenesis Associated With Spementioning

confidence: 99%

Section: Putative Therapeutic Options To Modulate Neuronal Mitochomentioning

confidence: 99%

Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

Uittenbogaard¹,

Chiaramello

2014

CPD

197

128

View full text Add to dashboard Cite

show abstract

“…These include bezafibrate and rosiglitazone and novel molecules such as resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) (71). …”

Section: Therapeutic Optionsmentioning

confidence: 99%

Medical Management of Hereditary Optic Neuropathies

Morgia

Carbonelli²,

Barboni

et al. 2014

Front. Neurol.

View full text Add to dashboard Cite

Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber’s hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated.

show abstract

“…However, a number of therapeutic approaches have been already applied or are still under development (15,26,(47)(48)(49)(50)(51). Some of these approaches are indicated below.…”

Section: Mitochondrial Medicinementioning

confidence: 99%

Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders

Papadopoulou

Tsiftsoglou

2011

Pharm Res

View full text Add to dashboard Cite

Protein therapy is considered an alternative approach to gene therapy for treatment of genetic-metabolic disorders. Human protein therapeutics (PTs), developed via recombinant DNA technology and used for the treatment of these illnesses, act upon membrane-bound receptors to achieve their pharmacological response. On the contrary, proteins that normally act inside the cells cannot be developed as PTs in the conventional way, since they are not able to "cross" the plasma membrane. Furthermore, in mitochondrial disorders, attributed either to depleted or malfunctioned mitochondrial proteins, PTs should also have to reach the subcellular mitochondria to exert their therapeutic potential. Nowadays, there is no effective therapy for mitochondrial disorders. The development of PTs, however, via the Protein Transduction Domain (PTD) technology offered new opportunities for the deliberate delivery of human recombinant proteins inside eukaryotic subcellular organelles. To this end, mitochondrial disorders could be clinically encountered with the delivery of human mitochondrial proteins (engineered via recombinant DNA and PTD technologies) at specific intramitochondrial sites to exert their function. Overall, PTD-mediated Protein Replacement Therapy emerges as a suitable model system for the therapeutic approach for mitochondrial disorders.

show abstract

Emerging therapeutic approaches to mitochondrial diseases

Cited by 37 publications

References 128 publications

Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

Medical Management of Hereditary Optic Neuropathies

Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders

Contact Info

Product

Resources

About