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Pharmacological strategies to enhance mitochondrial activity and their potential use in genetic mitochondrial disorders

Simón Serrano, Sonia (2017) MOBN01 20171
Degree Projects in Molecular Biology
Abstract
Mitochondria are the main organelles in eukaryotic cells involved in energy production together with their role in other mechanisms including intermediate metabolism, calcium signaling and apoptosis. Due to their importance in the correct function of the cell, genetic mitochondrial disorders can present a wide variability of symptoms, such as epilepsy, skeletal and cardiac myopathy and intellectual, endocrine and renal problems. We have investigated the potential and possible mechanism of action of β-lapachone, a natural quinone, and a novel β-lapachone analog to bypass mitochondrial complex I dysfunction and increase oxygen consumption coupled to ATP-synthase, decrease lactate production and induce mitochondrial biogenesis in healthy and... (More)
Mitochondria are the main organelles in eukaryotic cells involved in energy production together with their role in other mechanisms including intermediate metabolism, calcium signaling and apoptosis. Due to their importance in the correct function of the cell, genetic mitochondrial disorders can present a wide variability of symptoms, such as epilepsy, skeletal and cardiac myopathy and intellectual, endocrine and renal problems. We have investigated the potential and possible mechanism of action of β-lapachone, a natural quinone, and a novel β-lapachone analog to bypass mitochondrial complex I dysfunction and increase oxygen consumption coupled to ATP-synthase, decrease lactate production and induce mitochondrial biogenesis in healthy and complex I dysfunctional cells. The β-lapachone analog demonstrated to be more effective than β-lapachone after acute treatment, increasing oxygen consumption coupled to ATP-synthase and decreasing lactate production in cells with complex I inhibition. Chronic treatment of healthy cells and patient-derived sick cells with confirmed complex I dysfunction to β-lapachone or its analog, showed increased mitochondrial content and oxygen consumption coupled to ATP-synthase. (Less)
Popular Abstract
Mitochondria are the main specialized structures in eukaryotic cells involved in energy production. In addition, mitochondria play a critical role in intermediate metabolism, calcium signaling and cell death pathways. Therefore, patients affected by genetic mitochondrial disorders can present a wide variety of symptoms such as epilepsy, skeletal and cardiac myopathy and intellectual, endocrine and renal problems.
β-lapachone has been suggested as a potential treatment for genetic mitochondrial disorders, such as MELAS (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). It has been proposed to restore energy production at the mitochondria, reduce reactive oxygen species (ROS) levels and lactate production,... (More)
Mitochondria are the main specialized structures in eukaryotic cells involved in energy production. In addition, mitochondria play a critical role in intermediate metabolism, calcium signaling and cell death pathways. Therefore, patients affected by genetic mitochondrial disorders can present a wide variety of symptoms such as epilepsy, skeletal and cardiac myopathy and intellectual, endocrine and renal problems.
β-lapachone has been suggested as a potential treatment for genetic mitochondrial disorders, such as MELAS (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). It has been proposed to restore energy production at the mitochondria, reduce reactive oxygen species (ROS) levels and lactate production, increasing mitochondrial biogenesis and cell survival.
In this study, we evaluated β-lapachone and a novel β-lapachone analog as potential treatment strategies for genetic mitochondrial disorders. The potential of these compounds was assessed on cell level based on oxygen consumption, mitochondrial content and lactate production after treatment with the drugs.
The β-lapachone analog demonstrated to be more effective than β-lapachone itself after acute treatment increasing oxygen consumption linked to ATP production and decreasing lactate production in cells with simulated mitochondrial dysfunction. Chronic treatment of healthy and patient-derived sick cells to β-lapachone or its analog resulted in a tendency to increase mitochondrial content and oxygen consumption linked to ATP production, with the β-lapachone analog presenting a higher effect. To conclude, β-lapachone analog demonstrated potential as treatment for genetic mitochondrial disorders.

Master’s Degree Project in Molecular Biology 45 credits 2017
Mitochondrial Medicine & Neurovive Pharmaceutical
Supervisors: Eskil Elmér & Magnus Hansson (Less)
Please use this url to cite or link to this publication:
author
Simón Serrano, Sonia
supervisor
organization
course
MOBN01 20171
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8925127
date added to LUP
2017-09-08 16:13:14
date last changed
2017-09-08 16:13:14
@misc{8925127,
  abstract     = {Mitochondria are the main organelles in eukaryotic cells involved in energy production together with their role in other mechanisms including intermediate metabolism, calcium signaling and apoptosis. Due to their importance in the correct function of the cell, genetic mitochondrial disorders can present a wide variability of symptoms, such as epilepsy, skeletal and cardiac myopathy and intellectual, endocrine and renal problems. We have investigated the potential and possible mechanism of action of β-lapachone, a natural quinone, and a novel β-lapachone analog to bypass mitochondrial complex I dysfunction and increase oxygen consumption coupled to ATP-synthase, decrease lactate production and induce mitochondrial biogenesis in healthy and complex I dysfunctional cells. The β-lapachone analog demonstrated to be more effective than β-lapachone after acute treatment, increasing oxygen consumption coupled to ATP-synthase and decreasing lactate production in cells with complex I inhibition. Chronic treatment of healthy cells and patient-derived sick cells with confirmed complex I dysfunction to β-lapachone or its analog, showed increased mitochondrial content and oxygen consumption coupled to ATP-synthase.},
  author       = {Simón Serrano, Sonia},
  language     = {eng},
  note         = {Student Paper},
  title        = {Pharmacological strategies to enhance mitochondrial activity and their potential use in genetic mitochondrial disorders},
  year         = {2017},
}