text: Parkin regulates the proteasomal degradation of PARIS and PGC-1alpha-dependent mitochondrial biogenesis. (A) Normal physiological conditions that maintain mitochondrial homeostasis: PINK1 recruits parkin to the mitochondria, where these two proteins interact to eliminate abnormal mitochondria through mitophagy. Alterations in mitochondrial membrane potential (DeltaPsim; a key indicator of mitochondrial physiology and cell viability) initiate the PINK1-parkin cascade of events that lead to mitophagy. Furthermore, parkin ubiquitylates and thereby promotes proteasomal degradation of PARIS. Because PARIS represses the expression of PGC-1alpha, degradation of PARIS by parkin allows PGC-1alpha-dependent gene expression and enables mitochondrial biogenesis. Parkin seems to be an integral regulator of mitochondrial homeostasis, controlling both degradation and biogenesis. (B) Loss of parkin function as a result of familial mutations (in the case of AR-PD) or aging, environmental or cellular stress (in the case of sporadic PD) leads to the accumulation of abnormal mitochondria, owing to faulty mitophagy. In addition, PARIS accumulates and represses PGC-1alpha, preventing mitochondrial biogenesis. Loss of parkin function does not tip the balance between mitochondrial biogenesis and degradation to either side, but leads to a general breakdown of mitochondrial homeostasis that can ultimately lead to PD.
  
entities.text: ['proteasomal']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T1
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T2
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T3
entities.text: ['mitochondria']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T4
entities.text: ['mitochondria']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T5
entities.text: ['mitochondrial membrane']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T6
entities.text: ['proteasomal']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T7
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T8
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T9
entities.text: ['cellular']
entities.type: Cell
entities.entity_id: PMC-3124045-caption-01_T10
entities.text: ['mitochondria']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T11
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T12
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T13
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T14
entities.text: ['mitochondrial']
entities.type: Cellular_component
entities.entity_id: PMC-3124045-caption-01_T15
entities.text: ['cell']
entities.type: Cell
entities.entity_id: PMC-3124045-caption-01_T16