M˛tochondr˛al mechan˛c - internationalinnovation.com · Department of ˙ell B˜ology,...
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IN RECENT YEARS, mitochondrial dysfunction has been identified as playing a major role in ageing and age-related diseases. This is because the production of mitochondrial electron transport chain-derived reactive oxygen species increases in almost all age- related disorders. As a result, scientists have hypothesised that targeting mitochondrial dysfunction in ageing individuals could have protective health effects. Assistant Professor Patrick Bradshaw from the Department of Cell Biology, Microbiology and Molecular Biology at the University of South Florida, leads a research group dedicated to elucidating the role of mitochondrial dysfunction in both ageing and age-related ill health. With a view to identifying novel strategies for protecting mitochondrial function, Bradshaw and his team employ a highly multidisciplinary approach, combining the characterisation of isolated mitochondria from transgenic mouse models of neurodegeneration with metabolome and proteome profiling. Most recently, the group has used Caenorhabditis elegans nematodes as a model to study ageing-induced mitochondrial electron transport chain dysfunction and metabolic therapies to delay ageing. HEALTHY AGEING Bradshaw’s group is particularly interested in the mechanisms by which calorie restriction extends lifespan and delays the onset of age-related diseases. In cases of ageing and mitochondrial electron transport chain dysfunction, the ratio of an individual’s reduced nicotinamide adenine dinucleotide (NADH) to its oxidised form (NAD) becomes elevated, negatively impacting cellular metabolism. Bradshaw’s research suggests that calorie restriction can counteract this via its ability to stimulate mitochondrial biogenesis – a process that restores NAD levels to that required for a healthy cellular metabolism. High NAD levels are required for a group of cellular proteins called sirtuins to stimulate mitochondrial biogenesis. To date, Bradshaw and his colleagues have succeeded in elucidating a number of mechanisms underlying the protective effects of calorie restriction. One of the most significant may be the build-up of the ketone body beta-hydroxybutyrate (ßHB) within the body. “My lab was the first to show that ßHB can extend lifespan, not only though activating conserved stress response pathways, but also by modifying the way that DNA is packaged in the nucleus,” Bradshaw explains. “ßHB has been shown to inhibit a class of enzymes called histone deacetylases, leading to gene expression changes that protect against a variety of ageing-associated disorders, including inducing mitochondrial biogenesis.” Expanding on this finding, the researchers are currently investigating the effect of intermittent fasting, whereby an individual Researchers at the University of South Florida, USA, are identifying novel strategies for maintaining healthy mitochondrial function in ageing individuals, in an effort to stave off disease and neurodegeneration A natural approach How did you come to develop a research interest in mitochondrial dysfunction? During my graduate training, it was discovered that mitochondria are the main integrators of cellular information and the ‘point of no return’ in most cell death pathways. As most diseases are characterised by cell death in one tissue or another, this put mitochondrial research at the forefront for many types of degenerative diseases. This opened up a new field of studying mitochondrial function in neurodegenerative diseases. What are the specific aims of your research group? The main goal of the lab is to first identify genes that control ageing-related mitochondrial dysfunction – especially mitochondrial electron transport chain dysfunction – and then develop therapies to target these genes. To work toward this goal, we are performing high- throughput RNA interference (RNAi) screens in Caenorhabditis elegans nematodes, which are an excellent model for ageing-induced mitochondrial electron transport chain dysfunction. Why is the study of mitochondrial dysfunction in age-related diseases particularly important? It is becoming increasingly evident that the metabolic dysfunction that occurs with ageing may be a required step in the onset of almost all age-related diseases. Since mitochondria are the hub of cellular metabolism, maintaining their activity in a youthful state could help delay or prevent most age- related diseases. Assistant Professor Patrick Bradshaw is exploring the mechanisms by which mitochondrial dysfunction contributes to ageing and the onset and pathogenesis of age-related diseases Mitochondrial mechanic 40 INTERNATIONAL INNOVATION CELL BIOLOGY
Transcript of M˛tochondr˛al mechan˛c - internationalinnovation.com · Department of ˙ell B˜ology,...
IN RECENT YEARS, mitochondrial dysfunction has been identifi ed as playing a major role in ageing and age-related diseases. This is because the production of mitochondrial electron transport chain-derived reactive oxygen species increases in almost all age-related disorders. As a result, scientists have hypothesised that targeting mitochondrial dysfunction in ageing individuals could have protective health effects.
Assistant Professor Patrick Bradshaw from the Department of Cell Biology, Microbiology and Molecular Biology at the University of South Florida, leads a research group dedicated to elucidating the role of mitochondrial dysfunction in both ageing and age-related ill health.
With a view to identifying novel strategies for protecting mitochondrial function, Bradshaw and his team employ a highly multidisciplinary approach, combining the characterisation of isolated mitochondria from transgenic
mouse models of neurodegeneration with metabolome and proteome profi ling. Most recently, the group has used Caenorhabditis elegans nematodes as a model to study ageing-induced mitochondrial electron transport chain dysfunction and metabolic therapies to delay ageing.
HEALTHY AGEINGBradshaw’s group is particularly interested in the mechanisms by which calorie restriction extends lifespan and delays the onset of age-related diseases. In cases of ageing and mitochondrial electron transport chain dysfunction, the ratio of an individual’s reduced nicotinamide adenine dinucleotide (NADH) to its oxidised form (NAD) becomes elevated, negatively impacting cellular metabolism.
Bradshaw’s research suggests that calorie restriction can counteract this via its ability to stimulate mitochondrial biogenesis – a process that restores NAD levels to that required for a healthy cellular metabolism.
High NAD levels are required for a group of cellular proteins called sirtuins to stimulate mitochondrial biogenesis.
To date, Bradshaw and his colleagues have succeeded in elucidating a number of mechanisms underlying the protective effects of calorie restriction. One of the most signifi cant may be the build-up of the ketone body beta-hydroxybutyrate (ßHB) within the body. “My lab was the fi rst to show that ßHB can extend lifespan, not only though activating conserved stress response pathways, but also by modifying the way that DNA is packaged in the nucleus,” Bradshaw explains. “ßHB has been shown to inhibit a class of enzymes called histone deacetylases, leading to gene expression changes that protect against a variety of ageing-associated disorders, including inducing mitochondrial biogenesis.”
Expanding on this fi nding, the researchers are currently investigating the effect of intermittent fasting, whereby an individual
Researchers at the University of South Florida, USA, are identifying novel strategies for maintaining healthy mitochondrial function in ageing individuals, in an effort to stave off disease and neurodegeneration
A natural approach
How did you come to develop a research interest in mitochondrial dysfunction?
During my graduate training, it was discovered that mitochondria are the main integrators of cellular information and the ‘point of no return’ in most cell death pathways. As most diseases are characterised by cell death in one tissue or another, this put mitochondrial research at the forefront for many types of degenerative diseases. This opened up a new fi eld of studying mitochondrial function in neurodegenerative diseases.
What are the specifi c aims of your research group?
The main goal of the lab is to fi rst identify genes that control ageing-related mitochondrial dysfunction – especially mitochondrial electron transport chain dysfunction – and then develop therapies to target these genes. To work toward this goal, we are performing high-throughput RNA interference (RNAi) screens in Caenorhabditis elegans nematodes, which are an excellent model for ageing-induced mitochondrial electron transport chain dysfunction.
Why is the study of mitochondrial dysfunction in age-related diseases particularly important?
It is becoming increasingly evident that the metabolic dysfunction that occurs with ageing may be a required step in the onset of almost all age-related diseases. Since mitochondria are the hub of cellular metabolism, maintaining their activity in a youthful state could help delay or prevent most age-related diseases.
Assistant Professor Patrick Bradshaw is exploring the mechanisms by which mitochondrial dysfunction contributes to ageing and the onset and pathogenesis of age-related diseases
Mitochondrial mechanic
could help delay or prevent most age-could help delay or prevent most age-related diseases.
40 INTERNATIONAL INNOVATION
CELL BIOLOGY
fasts on alternative days, as a means of raising bloodstream ßHB levels.
AN ANSWER TO ALZHEIMER’SThe team is also carrying out research on specifi c age-related conditions such as Alzheimer’s disease, with the aim of identifying natural therapeutics that target mitochondrial disruption. Already, the researchers have produced evidence demonstrating that epigallocatechin-3-gallate (EGCG), the major fl avonoid in green tea, can reduce amyloid beta-induced mitochondrial dysfunction in Alzheimer’s. They are now working to identify the most potent metabolic derivatives of EGCG as well as developing intestine and blood-brain barrier-permeable ester forms of EGCG, with the aim of employing these as potential therapeutics.
The hormone melatonin is also a substance that has attracted Bradshaw’s interest, due to the fact that it is one of the most potent protectors of mitochondrial function produced in the body. The team’s
work in this area has revealed that roughly half of the mitochondrial protective effect of melatonin in an Alzheimer’s disease mouse model is due to the potent antioxidant and amyloid beta peptide anti-aggregating activities. The other half relies on melatonin binding its plasma membrane receptors to induce changes in cell signalling and gene expression.
EXPLORING EVERY ELEMENTThe natural therapies and novel approaches employed in Bradshaw’s innovative ageing and neurodegenerative disease research will continue to provide new insights into key mechanisms in age-associated disease. However, progress will not be achieved in silos: “If we are to overcome the complex challenges ahead, multipronged strategies will be key,” he concludes.
In recent years, mitochondrial dysfunction has been identifi ed as
playing a major role in ageing and age-related diseases
MITOCHONDRIAL DYSFUNCTION
OBJECTIVES• To determine the molecular mechanisms leading to
mitochondrial dysfunction with age
• To discover novel mechanisms that increase mitochondrial function using RNAi screens in Caenorhabditis elegans
• To develop therapies using metabolites and other natural products to improve mitochondrial function for the treatment of ageing and neurodegenerative diseases
KEY COLLABORATORSDr Stanley Stevens, University of South Florida, USA
Dr Paula Bickford, University of South Florida College of Medicine, USA
Dr James Olcese, Florida State University College of Medicine, USA
FUNDINGNational Institutes of Health
Winning the Fight Foundation
CONTACTDr Patrick BradshawAssistant Professor
Department of Biomedical SciencesJames H Quillen College of MedicineEast Tennessee State UniversityBox 70582Johnson City, TennesseeUSA 37614 1708
T +1 813 974 6180E [email protected]
www.biology.usf.edu/cmmb/faculty/pbradshaw
www.researchgate.net/profi le/Patrick_Bradshaw
ASSISTANT PROFESSOR PATRICK BRADSHAW started his career studying mitochondrial calcium transport and mitochondrial permeability transition in cell
death. He then shifted his focus to mitochondrial deoxynucleotide metabolism and mitochondrial toxicity of antiretroviral drugs. He is now investigating the mechanisms of mitochondrial dysfunction in ageing and neurodegeneration, and the development of metabolite-based therapies.
What signifi cant challenges are faced in the study of mitochondrial dysfunction and its relationship to age-associated diseases?
The biggest challenge is elucidating the molecular mechanisms of mitochondrial dysfunction in ageing and Alzheimer’s disease. A genetic approach is best suited for this problem, but this can be challenging in mammalian systems. A small interfering RNA (siRNA) screen in mammalian cell culture could identify regulators of mitochondrial electron transport chain function, but not ageing-induced modulators of mitochondrial function. Therefore, we have identifi ed C. elegans nematode worms as a model system of interest, as they rapidly lose mitochondrial electron transport chain function within one week of life.
The major regulator of mitochondrial biogenesis in mammalian systems –
peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) – does not, unfortunately, have an orthologue in C. elegans, so the mechanisms governing electron transport chain complex levels may be slightly different. Recently, it has been suggested that the transcriptional regulator SKN-1/Nrf2 may play a role in mitochondrial turnover in worms, so we will perform experiments to test this hypothesis.
How close are we to mitigating the Alzheimer’s epidemic?
I personally think that we are still around 50 years away from fi nding a cure for Alzheimer’s disease and other forms of dementia. We need to exert more effort into understanding the changes in the ageing brain, such as mitochondrial dysfunction, before we can fully understand and devise an effective therapy.
understanding the changes in the ageing brain, such as mitochondrial dysfunction, before we can fully understand and devise an
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