Murphy, M. P. and Hartley, R. C. (2018) Mitochondria as a therapeutic target for
common pathologies. Nature Reviews Drug Discovery, 17, pp. 865-886.
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http://eprints.gla.ac.uk/166107/
Deposited on: 13 August 2018
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Invited review for Nature Reviews Drug Discovery
Mitochondria as a therapeutic target for common pathologies
Michael P. Murphy
1
and Richard C. Hartley
2
1
MRC Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge CB2
0XY, UK
2
WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
Emails: richard.hartley@glasgow.ac.uk : mpm@mrc-mbu.cam.ac.uk
Abstract | Although the development of mitochondrial therapies has largely focused on
diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding
mitochondrial proteins, it has emerged that mitochondrial dysfunction also contributes to the
pathology of many common disorders, including neurodegeneration, metabolic disease, heart
failure, ischaemia-reperfusion injury and protozoal infections. Mitochondria therefore
represent an important drug target for these highly prevalent diseases. Several strategies
aimed at therapeutically restoring mitochondrial function are emerging and a small number of
agents have entered clinical trials. This review will discuss the opportunities and challenges
faced for the further development of a mitochondrial pharmacology for common pathologies.
Introduction
Mitochondria perform many key roles in the cell, most notably oxidative phosphorylation,
central carbon metabolism and the biosynthesis of intermediates for cell growth, but they are
also responsible for several other essential processes that determine cell function and fate
1,2
3-6
7
(FIG. 1 and Box 1). Consequently, mutations in nuclear or mtDNA genes that disrupt
mitochondrial function lead to devastating “primary” mitochondrial diseases
3,8-10
1,11
. Our
knowledge of how mitochondria function in the cell has expanded dramatically. It is now
clear that mitochondria participate in nearly all aspects of cell function, affecting processes
not traditionally linked with the organelle, including cancer, inflammation, metabolic
signalling, and cell death, transformation and fate
5,6
7
. Consequently, mitochondrial
dysfunction has been found to contribute to many common disorders, including
neurodegeneration, metabolic disease and heart failure
4,5,12,13
. These “secondary” mitochondrial
diseases can arise even if the proximal cause is not mitochondrial, for example when the
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initiating disease process disrupts mitochondrial function as a downstream effect
6,10,12,14-16
7
. Thus,
drugs designed to act on mitochondria may be effective therapies for a range of common
diseases, and could be more effective than when applied to the notoriously hard to treat
diseases that arise due to mutations in mitochondrial genes
3,12
14
7
10
. Importantly, drugs
designed to affect mitochondrial function can be applied to many highly prevalent diseases
and pathological processes, with important social, medical and economic impacts
2,17,18
. In
many cases progress in developing new therapeutic approaches for these common diseases
has been dispiritingly slow, as is illustrated by the lack of new drugs coming to market for
stroke or neurodegenerative diseases. Focusing on mitochondria offers a promising
alternative approach to developing new therapeutic options for these disorders
14,19,20
. Examples
of mitochondrial agents that are currently being, or have recently been, assessed in humans
include agents to replenish NAD
+
pools such as nicotinamide mononucleotide (NMN)
21
,
mitochondria-targeted protective compounds such as MitoQ
22,23
and Bendavia
24
, antioxidants
such as Coenzyme Q
10
25
and Cyclosporin A, an inhibitor of the mitochondrial permeability
transition pore
26
27
. Given that the development and application of drugs designed to affect
mitochondria is still in its infancy, this review will focus on the general principles, vast
potential and ongoing challenges for intervening at the mitochondrial level.
Rationale for targeting mitochondria
Disruption to mitochondrial bioenergetic and metabolic function can lead to many secondary
mitochondrial disorders (FIG. 1). Interestingly, common patterns regarding how
mitochondria contribute to the aetiology of disparate pathologies have emerged
5,14,28
. Important
among these are: the aberrant production of reactive oxygen species (ROS), calcium
dyshomeostasis, defective mitochondrial biogenesis, disruption to mitochondrial dynamics
and quality control, necrotic cell death through induction of the permeability transition pore
(MPTP), inappropriate activation or suppression of apoptosis, lowered cellular ATP/ADP
ratio, decreased NAD
+
levels and alterations to mitochondrial signaling pathways (FIG. 1)
14,28,29
7
. In many cases these different types of organelle dysfunction are linked mechanistically,
hence are often found together, and in addition they may contribute to disease by acute,
irreversible cell death, long term disruption to the role of mitochondria as signaling hubs, or
to the life-long accumulation of environmental damage that leads to a degenerative disorder
15
.
The details of how mitochondrial dysfunction leads to specific pathologies are discussed
below.
In short, there are three factors supporting the pursuit of mitochondria as a therapeutic
target for common pathologies. First, many prevalent diseases are “secondary” mitochondrial
disorders in that mitochondrial dysfunction contributes to the disease process or clinical
progression. Hence, targeting the organelle can improve patient outcome, even though
mitochondrial dysfunction may not be the primary driver of pathology. Second, mitochondria
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contribute to diverse pathologies through common pathways
10,14
, therefore a single therapeutic
approach may apply to multiple disorders. Finally, the common diseases where targeting
mitochondria show promise are of increasing medical, social and economic impact in our
aging population. Given that the development of new drugs for these disorders has been
frustratingly slow, new approaches are needed
30
31
32
.
Therapeutic approaches to mitochondria
There are a number of approaches aimed at modulating mitochondrial function in primary
and secondary mitochondrial diseases
3,9
. These include: behavioural interventions, such as
changes in diet or exercise
33
; exposure to hypoxia
34
; stem cell therapies
35
; replacing defective
mtDNA in an oocyte
36
; and supplementation of a tissue with exogenous mitochondria
37
.
Furthermore, there are many potential therapeutic strategies utilising gene therapies to deliver
corrected versions of a defective gene, or to ectopically express proteins designed to degrade
mutated mtDNA
38
or alter metabolism
39
. While all these approaches could lead to potential
treatments for common pathologies, their coverage is beyond the scope of this review, which
will focus on the general strategies for the development of small molecule therapies that can
modulate mitochondrial function.
Drugs can act directly on the mitochondria themselves, or affect the organelle
indirectly by binding to regulatory targets in the cytosol or nucleus
14,40
. An important aspect of
drugs that affect the organelle directly, is the ability to selectively target bioactive moieties to
mitochondria in vivo by conjugation to lipophilic cations or to peptides, which facilitates drug
effectiveness by enhancing potency, avoiding side effects and accelerating delivery
14,20,41,42
(Box
2).
There are five broad therapeutic strategies in which small molecules can be used to
affect mitochondria directly or indirectly in secondary mitochondrial diseases. These are: (i)
repairing or preventing damage to the organelle; (ii) inducing mitochondrial biogenesis; (iii)
enhancing organelle quality control by stimulating degradation of damaged mitochondria or
organelle components; (iv) co-opting mitochondrial function to induce cell death; or (v)
altering mitochondrial signaling pathways or metabolic processes. Below, we expand on
these, but of course it is important to note that many of these types of damage are linked and
that treating one mode of mitochondrial dysfunction often has a positive impact on others.
Protecting mitochondria
Mitochondrial dysfunction in diseases can arise from sustained damage to the organelle’s
protein, DNA and lipids
2,43-45
. Oxidative damage is frequently considered, due to the relatively
high level of ROS production by the mitochondrial respiratory chain and the susceptibility of
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the organelle to oxidative damage
46,47
. Carbon stress is another disruptor of mitochondrial
function that arises due to the high levels of activated acyl-CoAs in the mitochondrial matrix
that lead to non-enzymatic protein acylation, typically on lysine residues, that affects protein
function and proteostasis
44,45,48
.
A related common pathway of mitochondrial damage in many scenarios is the
depletion of NAD
+
, which can occur by activation of pathways that use up cellular and
mitochondrial NAD
+
pools, such as activation of poly (ADP-ribose) polymerases (PARPs),
mono ADP ribosyl transferases, and the cyclic ADP-ribose hydrolase CD38
49,50
51
52
. One
consequence of NAD
+
depletion is disruption of bioenergetic pathways. In addition, NAD
+
is
required for the reversal of lysine acylation by sirtuins, hence NAD
+
depletion also
contributes to an elevation of protein lysine acylation, disrupting signalling pathways that are
altered by lysine acylation and also contributing to carbon stress leading to the accumulation
of damaged and misfolded proteins. Of course, many other forms of damage occur, for
example disruption due to formation of the mitochondrial permeability transition pore
(MPTP), a large conductance channel in the inner membrane that is activated following
calcium accumulation in the presence of oxidative stress, leading to mitochondrial swelling
and subsequent cell death
53-55
.
Defects in mitochondrial proteostasis is another important form of mitochondrial
damage that contributes to a wide range of pathologies
7
56
57
. Normally the proteins within the
mitochondria are folded correctly and when they become damaged or miss-folded are either
refolded or rapidly degraded
7
56
57
. Thus, when correctly functioning, proteostasis prevents the
accumulation and aggregation of defective proteins within mitochondria, which would
severely disrupt organelle function. Mitochondria face a number of challenges in
maintaining proteostasis and maintaining the correct folding of proteins that are either
imported into, or translated within the organelle
57
. A further complication is that four of the
mitochondrial oxidative phosphorylation complexes contain polypeptides encoded by both
the nuclear and mitochondrial genomes, hence the relative levels of these polypeptides have
to be carefully matched to correctly assemble these complexes
57
. Finally, the mitochondrial
matrix is exposed to high levels of both oxidative and carbon stress, that can damage
proteins, rendering them less stable
57
. In dealing with these challenges the mitochondria does
not have a proteasome, nor the same heat shock protein complement as the cytosol. Instead,
it has its own repertoire of chaperones and proteases to maintain organelles proteostasis
57
7
56
.
The mitochondrial chaperones include mitochondrial heat shock protein 70 and 90 and the
matrix chaperonin complex composed of mitochondrial heat shock protein 60 and 10 that
help fold nascent proteins, or refold misfolded ones. In addition, mitochondria contain a
wide range of proteases that degrade misfolded proteins
58
7
56
. Mutations in these
mitochondrial proteases lead to the accumulation of misfolded proteins and dysfunctional
mitochondria in a number of diseases
58
. Furthermore, excessive oxidative damage, or protein
acylation due to carbon stress, cause protein missfolding and aggregation within