PINK1 function in health and disease

Abstract

The role of mitochondria in sporadic Parkinson's disease (PD) has been debated for a little over 20 years since the description of complex I deficiency in the substantia nigra pars compacta (SNpc) of PD patients. However, the identification of recessive pathogenic mutations in the pink1 gene in familial PD cases firmly re-ignited interest in the pathophysiology of mitochondria in PD. PINK1 is a putative mitochondrial serine/threonine kinase, which protects cells against oxidative stress induced apoptosis. The mechanism by which this is achieved and the effect of the pathogenic mutations has been an area of intensive research over the past five years. Significant progress has been made and, in this review, we summarize the physiological roles that have been assigned to PINK1 and the potential mechanisms behind pathogenesis.

Figure 1. PINK1 protects against oxidative stress induced apoptosis

In the absence of PINK1, mitochondrial and cytoplasmic ROS levels increase and cells showed impaired complex I activity within the electron transport chain. Phosphorylation of the TRAP1 protein by PINK1 is required for PINK1's pro-survival effect.

Figure 2. PINK1 and respiration

Loss of PINK1 function impairs mitochondrial respiration, results in reduced ATP production and increased ROS levels. The increase in ROS inhibits the glucose transporter and could induce mutations within mitochondrial DNA. Impairment of the glucose transporter reduces substrate delivery to complexes I and II of the respiratory chain. As a direct consequence, ATP synthase is forced to consume, rather than produce, ATP in order to maintain the mitochondrial membrane potential.

Figure 3. PINK1 and ubiquitin/protein folding/mitophagy

PINK1 interacts with the serine protease HtrA2, the E3-ligase Parkin and the molecular chaperone proteins Hsp90 and cdc37. The homologues of HtrA2 are involved in a protein quality control system. Whether HtrA2 is involved in PINK1 degradation has yet to be determined. PINK1's interaction with Parkin stabilizes PINK1 by interfering with PINK1 ubiquitination and subsequent degradation. PINK1 also forms a functional E3 ligase complex with Parkin and DJ-1 to promote the degradation of misfolded Parkin substrates via the UPS. In addition, the interaction between PINK1 and the Hsp90–cdc37 complex results in the stabilization of the full length PINK1 and its 42 kDa cleavage product. The UPS is critically dependent on ATP. Therefore, since loss of PINK1 results in reduced ATP levels, the UPS function may be impaired resulting in the accumulated misfolded and ubiquitinated proteins being removed by autophagy.

Figure 4. PINK1 in mitochondrial fission/fusion

The balance between mitochondrial fission and fusion is affected by PINK1. PINK1 functions as a potential pro-fusion protein in mammals and a pro-fission protein in Drosophila. Loss of PINK1 results in increased fission in mammalian mitochondria. This phenotype can be rescued by overexpression of a dominant negative DRP-1 protein. In contrast, loss of PINK1 function drives mitochondrial fusion in Drosophila. This phenotype can be rescued by overexpression of wild type DRP-1.

Figure 5. PINK1 and mitochondrial trafficking

PINK1 interacts with Miro and Milton and may play a role in anterograde mitochondrial transport within cells. It is unclear whether PINK1 and Miro and Milton interact en route to the mitochondria or whether they interact via a possible adapter protein at the mitochondria. Loss of PINK1 function increases calcium levels within the cytosol and this is known to inhibit mitochondrial motility.

Figure 6. PINK1 in calcium signalling

PINK1 directly regulates calcium efflux from mitochondria via the mitochondrial sodium/calcium exchanger. The resulting mitochondrial overload stimulates ROS production. The increase in ROS inhibits the glucose transporter and reduces the substrate supply to the respiratory chain. The combined calcium and ROS increase lowers the mitochondrial membrane potential and results in opening of the mitochondrial PTP pore at a lower stimulus. Opening of the mPTP releases pro-apoptotic factors such as cytochrome c from the mitochondria and induces apoptosis.