Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity

In combination with studies of post-mortem Parkinson’s disease (PD)
brains, pharmacological and genetic models of PD have suggested
that two fundamental interacting cellular processes are impaired –
proteostasis and mitochondrial respiration. We have re-examined the
role of mitochondrial dysfunction in lymphoblasts isolated from
individuals with idiopathic PD and an age-matched control group. As
previously reported for various PD cell types, the production of reactive
oxygen species (ROS) by PD lymphoblasts was significantly elevated.
However, this was not due to an impairment of mitochondrial
respiration, as is often assumed. Instead, basal mitochondrial
respiration and ATP synthesis are dramatically elevated in PD
lymphoblasts. The mitochondrial mass, genome copy number and
membrane potential were unaltered, but the expression of indicative
respiratory complex proteins was also elevated. This explains the
increased oxygen consumption rates by each of the respiratory
complexes in experimentally uncoupled mitochondria of iPD cells.
However, it was not attributable to increased activity of the stress- and
energy-sensing protein kinase AMPK, a regulator of mitochondrial
biogenesis and activity. The respiratory differences between iPD and
control cells were sufficiently dramatic as to provide a potentially
sensitive and reliable biomarker of the disease state, unaffected by
disease duration (time since diagnosis) or clinical severity.
Lymphoblasts from control and PD individuals thus occupy two
distinct, quasi-stable steady states; a ‘normal’ and a ‘hyperactive’
state characterized by two different metabolic rates. The apparent
stability of the ‘hyperactive’ state in patient-derived lymphoblasts in the
face of patient ageing, ongoing disease andmounting disease severity
suggests an early, permanent switch to an alternative metabolic steady
state. With its associated, elevated ROS production, the ‘hyperactive’
statemight not cause pathology to cells that are rapidly turned over, but brain cells might accumulate long-term damage leading ultimately to
neurodegeneration and the loss of mitochondrial function observed
post-mortem. Whether the ‘hyperactive’ state in lymphoblasts is a
biomarker specifically of PD or more generally of neurodegenerative
disease remains to be determined.