Biomedical Engineering Reference
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production. Given their many functions, mitochondria have been associated with
several human neuromuscular (e.g. mitochondrial DNA (mtDNA)) and metabolic
diseases, as well as with cancer progression (Holt et al.
1988
; Harding
1991
;
de Moura et al.
2010
; Breunig et al.
2008
; Andre et al.
2006
). Schaefer et al.
approximates that around 1 in 10,000 people have clinically manifest mtDNA dis-
ease, making this one of the most common inherited neuromuscular disorders. In
addition, 16.5 in 100,000 people younger than 65 are at risk for development of
mtDNA disease (Schaefer et al.
2008
). These estimates confirm that mtDNA dis-
eases can represent a common cause of chronic morbidity that is more prevalent
than what previously estimated.
The mitochondrion is composed of an outer mitochondrial membrane (OMM),
intermembrane space (IMS), inner mitochondrial membrane (IMM), and matrix.
The mitochondrion also contains special translocases of the outer membrane (TOM)
and translocases of the inner mitochondrial membrane (TIM) which are involved in
mitochondrial trafficking. Mitochondria contain several unique proteins, many of
which are coded by the nucleus and must be imported from the cytosol into the
organelle. Mitochondrial precursor proteins are delivered to the organelle by virtue
of specific mitochondrial targeting signals. These signals are relatively divergent in
nature, but are all recognized by the specialized receptor proteins, which are located
in the OMM and expose their receptor domains to the cytosol. The receptors deliver
the precursor proteins to the translocation channel of the TOM complex, through
which the pre-proteins cross the OMM. The TOM complex itself is sufficient for
translocation of a small subset of OMM proteins and some IMS proteins. For trans-
location of all other mitochondrial pre-proteins, the TOM complex cooperates with
other mitochondrial translocases. According to Mokranjac et al., six complex
molecular machines, i.e. protein translocases, mediate this process (Mokranjac and
Neupert
2005
). Studies involving purified TOM40 of
Neurospora crassa
suggest a
pore diameter of 2.5 nm (Ahting et al.
2001
). The TIM23 complex is a major trans-
locase in the IMM. It is an energy-dependent complex that facilitates pre-protein
translocation across the IMM and insertion into the IMM (Fig.
5
).
Although there are currently no drug therapies that target the mitochondria, there
are some anticancer agents (paclitaxel, vinblastine, lonidamine, etoposide, and
arsenic trioxide) already in clinical use that permeabilize mitochondria (Breunig
et al.
2008
; Andre et al.
2006
). Overall, these drugs aim to activate the cell-death
machinery in cancer cells by inhibiting metabolic tumor-specific alterations or by
stimulating mitochondrial membrane permeabilization. In clinical trials, therapeu-
tics like Lonidamine, Gadolinium Texaphyrin, Mangafodipir show few side effects,
whereas drugs like 2-deoxy-D-glucose and ANT1 (adenine nucleotide translocase 1)
or ANT3 show significant side effects, such as compromised glycolytic metabolism
of the brain and of the heart (Fulda et al.
2010
). These anticancer agents are toxic
due to nonspecific targeting and thus hinder therapeutic efficacy. To avoid severe
side effects and improve efficacy, drugs should not only be delivered to the correct
cell, but ideally also to the correct subcellular organelle.
Despite some challenges in mitochondrial targeting following systemic admin-
istration, which include: (1) immune clearance of nanoparticles (2) traversing the
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