Mitochondrial biogenesis: pharmacological approaches.

TLDR: The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions.

Abstract: Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an important mitochondrial component both on their onset and on their development. This is the case of type 2 diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about the origin of insulin resistance Monica Zamora and Josep A. Villena (Department of Experimental and Health Sciences, Universitat Pompeu Fabra / Laboratory of Metabolism and Obesity, Universitat Autonoma de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired (mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or the consequence of insulin resistance, it has been widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes. Thus restoring oxidative capacity by increasing mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential pharmacological targets and opens the perspectives for the design of suitable treatments for insulin resistance. In addition some of the current used strategies could be used to treat insulin resistance such as lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions (thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK activators, ERR activators). Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and morphology [1]. Parkinson´s Disease (PD) is a very good example of this important mitochondrial component on neurodegenerative diseases. Anuradha Yadav, Swati Agrawal, Shashi Kant Tiwari, and Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with special focus on the role of oxidative stress and bioenergetic deficits. These alterations may have their origin on pathogenic gene mutations in important genes such as DJ-1, -syn, parkin, PINK1 or LRRK2. These mutations, in turn, may cause defects in mitochondrial dynamics (key events like fission/fusion, biogenesis, trafficking in retrograde and anterograde directions, and mitophagy). This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials. They highlight a dual effect of PGC-1α expression on PD prognosis. Whereas a modest expression of this transcriptional co-activator results in positive effects, a moderate to substantial overexpession may have deleterious consequences. As strategies to induce PGC-1α activation, these authors remark the possibility to activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and -lipoic acid. Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental disorders. In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello (Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development. A mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control systems and mitochondrial biogenesis. Concerning the signaling pathways leading to mitochondrial biogenesis this review highlights the implication of different regulators such as AMPK, SIRT1, PGC-1α, NRF1, NRF2, Tfam, etc. on the specific case of neuronal development, providing examples of diseases in which these pathways are altered and transgenic mouse models lacking these regulators. A common hallmark of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease) is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. Among the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK (AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). This article also presents a review of the current animal and cellular models useful to study mitochondriogenesis. Although it is known that many neurodegenerative and neurodevelopmental diseases are originated in mitochondria, the regulation of mitochondrial biogenesis has never been extensively studied. (ABSTRACT TRUNCATED)

Full text

Mitochondrial Biogenesis: Pharmacological Approaches
Item Type Editorial
Authors Valero-Grinan, Teresa M.
Citation Valero-Grinan T (2014) Editorial (Thematic Issue: Mitochondrial
Biogenesis: Pharmacological Approaches). Current
Pharmaceutical Design. 20(35): 5507-5509.
Rights © 2014 Bentham Science. Reproduced in accordance
with the publisher's self-archiving policy. The published
manuscript is available at EurekaSelect via https://
doi.org/10.2174/138161282035140911142118.
Download date 10/08/2022 07:20:00
Link to Item http://hdl.handle.net/10454/13341

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Link to original published version: https://doi.org/10.2174/138161282035140911142118
Citation: Valero-Grinan T (2014) Editorial (Thematic Issue: Mitochondrial Biogenesis:
Pharmacological Approaches). Current Pharmaceutical Design. 20(35): 5507-5509.
Copyright: © 2014 Bentham Science. Reproduced in accordance with the publisher's self-
archiving policy. The published manuscript is available at EurekaSelect via
https://doi.org/10.2174/138161282035140911142118

Mitochondrial Biogenesis: Pharmacological Approaches
Editorial: Valero, Teresa. Dr. rer. nat.
Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that
organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis
occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events
[1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be
produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to
exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial
diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their
individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a
potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major
ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes
such as apoptosis, detoxification, Ca
2+
buffering, etc. This pivotal role makes mitochondria a potential target
to treat a great variety of diseases.
Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of
approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent
discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative
diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new
pharmacological targets and natural therapies. It contributes to the field by covering and gathering the
scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis.
There are several diseases that have a mitochondrial origin such as chronic progressive external
ophthalmoplegia (CPEO) and the Kearns-Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers
(MERRF), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), Leber’s
hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis
pigmentosa (NARP), and Leigh’s syndrome. Likewise, other diseases in which mitochondrial dysfunction
plays a very important role include neurodegenerative diseases, diabetes or cancer.
Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of
the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce
further mtDNA mutations. The work by Yu -Ting Wu, Shi-Bei Wu, and Yau-Huei Wei
(Department of
Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the
aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt
mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory
mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and
overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways
observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in
mitochondrial diseases are described (PGC-1α, Sirtuins, AMPK). Several pharmacological strategies to
trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-
PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or
resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet
(dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q
10
,
MitoQ
10
and other
mitochondria-targeted antioxidants
,
N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B,
sodium pyruvate or α-lipoic acid.
As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an
important mitochondrial component both on their onset and on their development. This is the case of type 2
diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance
accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about
the origin of insulin resistance Mónica Zamora and Josep A. Villena (Department of Experimental and
Health Sciences, Universitat Pompeu Fabra /
Laboratory of Metabolism and Obesity, Universitat Autònoma
de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired
(mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin

resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on
the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or
the consequence of insulin resistance, it has been widely observed that improving mitochondrial function
also improves insulin sensitivity and prevents type2 diabetes. Thus restoring oxidative capacity by increasing
mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers
trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential
pharmacological targets and opens the perspectives for the design of suitable treatments for insulin
resistance. In addition some of the current used strategies could be used to treat insulin resistance such as
lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions
(thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK
activators, ERR activators).
Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum
of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and
morphology [1]. Parkinson´s Disease (PD) is a very good example of this important mitochondrial
component on neurodegenerative diseases. Anuradha Yadav, Swati Agrawal,
Shashi Kant Tiwari,
and
Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and
Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with
special focus on the role of oxidative stress and bioenergetic deficits. These alterations may have their origin
on pathogenic gene mutations in important genes such as DJ-1, α-syn, parkin, PINK1 or LRRK2. These
mutations, in turn, may cause defects in mitochondrial dynamics (key events like fission/fusion, biogenesis,
trafficking in retrograde and anterograde directions, and mitophagy). This work reviews different strategies
to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an
emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and
mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical
trials. They highlight a dual effect of PGC-1α expression on PD prognosis. Whereas a modest expression of
this transcriptional co-activator results in positive effects, a moderate to substantial overexpession may have
deleterious consequences. As strategies to induce PGC-1α activation, these authors remark the possibility to
activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and
bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by
triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by
carnitine and α-lipoic acid.
Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental
disorders. In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello
(Department
of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health
Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal
differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic
strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development. A
mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control
systems and mitochondrial biogenesis. Concerning the signaling pathways leading to mitochondrial
biogenesis this review highlights the implication of different regulators such as AMPK, SIRT1, PGC-1α,
NRF1, NRF2, Tfam, etc. on the specific case of neuronal development, providing examples of diseases in
which these pathways are altered and transgenic mouse models lacking these regulators. A common hallmark
of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease)
is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. Among
the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of
PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK
(AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). This
article also presents a review of the current animal and cellular models useful to study mitochondriogenesis.
Although it is known that many neurodegenerative and neurodevelopmental diseases are originated in
mitochondria, the regulation of mitochondrial biogenesis has never been extensively studied. In order to find
effective treatments to these up to date uncured diseases, comprehensive studies are therefore necessary on
the control mechanisms of mitochondrial biogenesis, on the dynamic mitochondrial balance (fusion, fission,
mitophagy and trafficking) and on the potential crosstalk among different biological processes, as expressed
by the authors, along with the development of novel animal models to appropriately study this
mitochondriogenesis.

A switch in bioenergetics is necessary for cancer development. Thus the control of mitochondrial
bioenergetics and dynamics could be useful as potential interventions on cancer treatments. Pilar Roca, Jorge
Sastre-Serra, Mercedes Nadal-Serrano, Daniel Gabriel Pons, Mª del Mar Blanquer-Rosselló and Jordi Oliver
(Institut d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Spain) [8] describe
the regulation of estrogen receptors, their implication on breast cancer, on mitochondrial biogenesis,
mitochondrial function, and ROS production. It deeply reviews the group of natural compounds intimately
related to estrogen receptors, flavonoids, and their application in cancer treatment and research, their action
mechanisms, etc. giving an emphasis on the differences found in the response depending on the doses,
timing, absorption, metabolism and hormonal status for the design of new strategies to treat breast cancer.
In the search of new targets for therapies based on targeting mitochondrial biogenesis it is of extreme
importance to understand the pathways involved as well as the mediators that promote these signaling
pathways. Fabian Sanchis-Gomar, José Luis García-Giménez, Mari Carmen Gómez-Cabrera and Federico V.
Pallardó (Department of Physiology, University of Valencia / CIBERER / INCLIVA, Spain) [9] make a broad
review on the current knowledge in this field, as well as about the diseases which course with alterations on
the mitochondrial biogenesis pathways. Although the knowledge on specific treatments based on
mitochondriogenesis is still poor, several drugs that are currently in the market present features potentially
useful to trigger mitochondriogenesis for the treatment of specific diseases. This review compiles most of
them, making an emphasis on the observed side effects of these drugs and the lack of selectivity of these
strategies due to the fact that mitochondriogenesis is a ubiquitous phenomenon. Far from being a backward,
this may constitute a challenge for designing more tissue-specific therapeutic approaches.
The study of mitochondrial biogenesis is especially complex, due to the endosymbiotic evolutionary origin
of this organelle. Mitochondria are the most complex and unique organelles: in which eukaryotic and
prokaryotic mechanisms coexist, they possess an inner and an outer membrane, own small genome and they
suffer continuous fusion and fission events. Moreover, along with endosymbiosis, novel mitochondrial
biogenesis pathways have evolved [1]. In order to extend our knowledge about underlying mechanisms via
which mitochondriogenesis in different tissues is induced, it is crucial to use the proper techniques to
measure mitochondrial mass. In living cells, the regulation of mitochondrial content or mitochondrial mass
depends on the subtle balance between mitochondrial biogenesis, mitochondrial degradation (mitophagy)
and mitochondrial dynamics (fusion, fission). Karl J. Tronstad, Marco Nooteboom, Linn I. H. Nilsson, Julie
Nikolaisen, Maciek Sokolewicz, Sander Grefte, Ina K.N. Pettersen, Sissel Dyrstad, Fredrik Hoel,
Peter
H.G.M. Willems and Werner J.H. Koopman (Department of Biomedicine, University of Bergen, Norway /
Department of Biochemistry Radboud University Medical Centre, The Netherlands) [10] describe the
mechanism that maintains this equilibrium and the available techniques to quantify mitochondrial
morphology and content. After reviewing the advantages and disadvantages of the most common techniques
and strategies (measuring oxygen consumption, biochemical biomarkers or by electron microscopy), we can
find in this work a deep analysis on fluorescence microscopy for the detection of mitochondrial content, its
visualization, quantitation and interpretation of results both in 2D and in 3D imaging, along with available
software and strategies developed by this group and others. This work can be of great help at the time to
choose a technique to study mitochondrial biogenesis in a specific cell type. In addition, we can also find a
table with several drugs known to affect mitochondriogenesis.
Free radicals have been widely considered as harmful for the cellular structures and promoters of senescence.
However, they also act as second messengers by triggering signals which induce gene expression. Indeed,
endogenous free radicals can trigger mitochondriogenesis. Hagir B. Suliman, and Claude A. Piantadosi
(Departments of Anesthesiology, Duke Cancer Institute, Medicine and Pathology, Duke University Medical
Center, USA) [11] broadly review the effect of these free radicals on mitochondriogenesis during
inflammation. In periods of active inflammation due to an acute tissue damage, mitochondria are frequently
damaged by oxidative and nitrosative stress. The elevated levels of endogenous free radicals trigger
mitochondriogenesis and mitophagy in a compensatory manner. This is the case of the NO/cGMP/PGC-1α
axis, the CO/HO-1 system and the HS
2
/Akt/NRF-1/-2 axis. Several well known drugs can interact with those
and other signaling pathways to induce mitochondriogenesis like NO donors, CO releasing molecules,
triterpenoids, erythropoietin, thiazolidinedione drugs, metformin, AICAR and several natural compounds
(including nutrients and scavengers). Thus inducing mitochondrial biogenesis and quality control represents
a potential valuable approach for the development of new therapies for those diseases which course with

Frequently asked questions

Q1. What is the role of mitochondrial dysfunction in diseases?

in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. 

Q2. What is the role of mitochondria in the development of the body?

In periods of active inflammation due to an acute tissue damage, mitochondria are frequently damaged by oxidative and nitrosative stress. 

Q3. What is the role of mitochondrial biogenesis in Parkinson s Disease?

A mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control systems and mitochondrial biogenesis. 

Q4. What is the role of mitochondria in the cell mediating processes?

as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca 2+ buffering, etc. 

Q5. What is the common hallmark of Alzheimer s Disease?

A common hallmark of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease) is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. 

Q6. What is the role of mitochondria in the regulation of mitochondrial mass?

In living cells, the regulation of mitochondrial content or mitochondrial mass depends on the subtle balance between mitochondrial biogenesis, mitochondrial degradation (mitophagy) and mitochondrial dynamics (fusion, fission). 

Q7. What is the significance of mitochondrial biogenesis in modern neurochemistry?

Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and morphology [1]. 

Q8. What are the other strategies to enhance mitochondrial biogenesis?

Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and α-lipoic acid. 

Q9. What are the main strategies used to trigger the AMPK signaling cascades?

Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPARPGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. 

Q10. What are the notable antioxidants/peptides in clinical trials?

Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials. 

Q11. What are the common strategies used to trigger mitochondrial biogenesis?

Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10, MitoQ10 and other mitochondria-targeted antioxidants, N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or α-lipoic acid. 

Q12. What are some interventions that can be used to increase the lifespan of mitochondria?

Some interventions include the non-pharmacological control of mitochondrial biogenesis and dynamics by caloric restriction, endurance exercise and dietary supplementation with a mixture of essential amino acids enriched in branched-chain amino acids (BCAAs). 

Q13. What are the main pathways that can interact with mitochondrials?

Several well known drugs can interact with those and other signaling pathways to induce mitochondriogenesis like NO donors, CO releasing molecules, triterpenoids, erythropoietin, thiazolidinedione drugs, metformin, AICAR and several natural compounds (including nutrients and scavengers). 

Q14. What is the main focus of the work?

The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. 

Q15. What is the role of mitochondria in mitochondriogenesis?

Considering specific mitochondria, it has been observed that a modest production of free radicals by this organelle can act as second messengers to trigger mitochondriogenesis [15]. 

Q16. What is the promising strategy to ameliorate mitochondrial diseases?

Among the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK (AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). 

Q17. What are the main diseases in which mitochondrial dysfunction plays a very important role?

other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. 

Q18. What are the common mitochondrial alterations?

These alterations may have their origin on pathogenic gene mutations in important genes such as DJ-1, α-syn, parkin, PINK1 or LRRK2. 

Q19. What is the role of mitochondria in the development of new therapeutic strategies?

Enzo Nisoli and Alessandra Valerio (Center for Study and Research on Obesity / Department of Medical Biotechnology and Translational Medicine, University of Milan / Department of Molecular and Translational Medicine, University of Brescia, Italy) [12] review the contribution of mitochondria and other organelles on aging and anti aging-strategies, pointing out the interplay between organelles as a potential target for the design of new therapeutic interventions against agerelated diseases and to increase life- and healthspan. 

Q20. What are the pathways that are related to mitochondrial biogenesis?

The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC-1α, Sirtuins, AMPK). 

Q21. What is the role of mitochondrial dysfunction in PD?

Anuradha Yadav, Swati Agrawal, Shashi Kant Tiwari, and Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with special focus on the role of oxidative stress and bioenergetic deficits.