Biology Reference
In-Depth Information
DO MITOCHONDRIA PLAY A ROLE IN LIPODYSTROPHY?
Fatty acids derived from hydrolysis of triglicerides circulate in the plasma
bound to albumin and are usually removed from blood into mitochondria, to
undergo a process called beta-oxidation that ultimately generates ATP. This
process is preceded by their transformation into acetyl-CoA via an ATP-
dependent reaction that takes place in the microsomal system. Alterations of
lipid metabolism provoked by a mitochondrial dysfunction could impair such a
biochemical pathway, and thus could have a crucial role in the phenomenon of
fat redistribution, or lipodystrophy, an important pathology that has been
linked to highly active antiretroviral therapy (HAART ). It has been hypothe-
sized that, in some patients, HAART can be responsible for the onset of a
characteristic syndrome named lipodystrophy, with peripheral fat wasting and
central adiposity ( Brinkman et al., 1999). HIV-1 protease inhibitors are gener-
ally believed to be the causal agents, although the syndrome has also been ob-
served with protease-inhibitor-sparing regimens. The mitochondrial toxicity of
nucleoside-analog reverse-transcriptase inhibiting ( NRTI ) antiretroviral drugs
could play an essential part in the development of this lipodystrophy, similar to
the role of mitochondrial defects in the development of multiple symmetrical
lipomatosis.
Some years ago, it was shown that a widely used NRTI with a crucial role in
anti-HIV therapy, i.e., zidovudine (AZT ), was able to act directly on mitochon-
dria because of its capability to integrate into the mitochondrial genome, in a
manner similar to what occurs for the nuclear genome. However, if damages to
nuclear DNA can be repaired in most cells by an adequate set of enzymes, such
activity, which has been acquired during evolution, is likely not present (or, at
least, is not particularly e½cient) in mitochondrial DNA. As a consequence,
damages to mitochondrial DNA, a molecule that is present in several copies in
one single organelle and contains genes for crucial enzymes of the respiratory
chain, cannot always be repaired and, in turn, can be responsible for alterations
in energy metabolism.
Concerning lipodystrophy, scientists have only recently devoted attention to
the mechanisms of action of protease inhibitors ( PI ), the most recent drugs
used for HAART, as well as to their interaction with other antiretroviral com-
pounds. Indeed, if on the one hand it is known that some drugs not belonging
to the PI category can directly a¨ect mitochondria (as described above), on the
other hand it has been shown that the PI are also able to induce apoptosis in
adipocytes, a phenomenon that is mediated by the intracytoplasmic block of
retinoic-acid binding protein-1, normally responsible for cell di¨erentiation. PI
are also capable of interfering with the synthesis of 9-cis retinoic acid, catalyzed
by cytochrome P450-3A. Both these mechanisms, which basically concern reti-
noic acid signaling, clearly cannot explain the onset of lipodystrophy in patients
who have never been treated with PI. Thus, other drugs, and in particular
NRTI, have been claimed to be directly responsible.
