Another pathway by which protease inhibitors might contribute towards the fat redistribution syndrome seen in people taking antiretroviral therapy has been uncovered by researchers from Purdue University, Indiana, and the US National Institutes of Health.
The group found that several protease inhibitors can impair the activity of mitochondria, bodies within cells which process energy. They are often described as the powerhouses of the cell, and damage to mitochondria, or impairment of mitochondrial activity, can have a wide range of consequences. Problems include the development of lactic acidosis (a potentially fatal side effect of nucleoside analogue treatment in HIV disease) and the development of fat accumulation in Madelung’s disease as a consequence of mutations in mitochondrial DNA.
Nucleoside analogues impair mitochondrial DNA polymerase gamma, and mitochondrial DNA levels are reduced in people who develop NRTI-related hyperlactatemia, and structural changes in mitochondria found in fat tissue of people with lipodystrophy have also been reported by some research groups.
However, this study found that protease inhibitors affected another process within the mitochondrion.
"In this study, we have demonstrated that protease inhibitors can directly affect an enzyme called mitochondrial processing protease (MPP), which can lead to mitochondrial dysfunction - possibly contributing to the development of syndromes such as lipodystrophy," said Lauren Wood, M.D., of the National Cancer Institute.
The study was carried out using a yeast culture which is an accepted surrogate for measuring impairment of mitochondrial processing in mammals. The group found that indinavir and amprenavir can impair processing, but it was impossible to assess the effect of ritonavir because chemicals used to make ritonavir more soluble in water affected the experiment. Saquinavir had a weaker effect and nelfinavir was not tested.
Impaired processing would prevent mitochondria from growing, and the authors argue that mitochondrial DNA mutations seen in some studies of lipodystrophy patients could be attributable to the effect of protease inhibitors at this early stage in the cell’s growth and life cycle.
While protease inhibitors alone do not necessarily cause lipodystrophy, the combination of direct effects on mitochondria by both protease inhibitors and NRTIs may lead to the condition. Moreover, as a class of drugs, protease inhibitors are highly hydrophobic (water insoluble), and hence may be concentrated in fatty tissues and have a greater impact on mitochondria in those tissues with chronic exposure.
“Our results provide a potentially unifying theme in the multifactorial pathophysiology of lipodystrophy”, the authors said.
The researchers do not know to what degree MPP inhibition correlates with mitochondrial change or disruption, nor if what they found with isolated mitochondria, in this test tube study, actually occurs in patients using the drug. It is known, however, that both NRTIs and protease inhibitors have direct effects on fat cells, and mitochondrial abnormalities in fat tissue have been described in patients with lipodystrophy.
According to Steven J. Zullo, Ph.D., of NIST (formerly of the National Institute of Mental Health), "Many drugs can adversely affect mitochondria. This study highlights the importance of evaluating the potential short- and long-term effects of drugs on mitochondria before they are recommended for widespread use."
Researchers say that future studies should look at the effect of MPPs on the fatty tissue in patients as opposed to the test tube experiments done for this study. They also recommend that when scientists design new HIV/AIDS drugs, they consider the effects that the drugs might have on mitochondria, and attempt to minimize adverse effects.
However, the findings are likely to provoke controversy, since attempts to identify the contribution of mitochondrial toxicity associated with nucleoside analogue treatment have produced conflicting results and strong disagreement amongst researchers over the extent to which mitochondrial toxicity is responsible for any aspect of the lipodystrophy syndrome.
These controversies are discussed in more detail in
Possible causes of body fat and metabolic changes elsewhere on this site.
Mukhopadhyay A et al. In vitro evidence of inhibition of mitochondrial protease processing by HIV-1 protease inhibitors in yeast: a possible contribution to lipodystrophy syndrome. Mitochondrion 2 (Sept): 54-62, 2002.