Neuronal hypoxia disrupts mitochondrial fusion

Abstract

Brain ischemia/reperfusion injury results in death of vulnerable neurons and extensive brain damage. It is well known that mitochondrial release of cytochrome c (cyto c) is a hallmark of neuronal death, however the molecular events underlying this release are largely unknown. We tested the hypothesis that cyto c release is regulated by breakdown of the cristae architecture maintenance protein, optic atrophy 1 (OPA1), located in the inner mitochondrial membrane. We simulated ischemia/reperfusion in isolated primary rat neurons and interrogated OPA1 release from the mitochondria, OPA1 oligomeric breakdown, and concomitant dysfunction of mitochondrial dynamic state. We found that ischemia/reperfusion induces cyto c release and cell death that corresponds to multiple changes in OPA1, including: (i) translocation of the mitochondrial fusion protein OPA1 from the mitochondria to the cytosol, (ii) increase in the short isoform of OPA1, suggestive of proteolytic processing, (iii) breakdown of OPA1 oligomers in the mitochondria, and (iv) increased mitochondrial fission. Thus, we present novel evidence of a connection between release of cyto c from mitochondria and disruption of the mitochondrial fusion.

Mitochondrial dynamics in neuronal injury, development and plasticity

“…In vitro models of cerebral ischemia confirm these findings, as glutamate excitotoxicity (Kumari et al, 2012;Niizuma et al, 2010) and hypoxia (Sanderson et al, 2015) on their own can induce mitochondrial fragmentation. The relationship between mitochondrial fission and ischemic injury appears more than correlative, as inhibition of Drp1 with the small-molecule inhibitor mdivi-1 was shown by several groups to decrease infarct volume following MCAO (Grohm et al, 2012;Li et al, 2015;Zhang et al, 2013).…”

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

“…In addition, under increased oxidative stress after exposure to neurotoxic glutamate, mitochondrial fusion protein OPA1, normally present in the mitochondrial inner membrane, is discharged to cytosol with concomitant release of cytochrome c. These events are accompanied by mitochondrial fragmentation and apoptosis of HT22 cells while an antioxidant tocopherol significantly prevented these events (Sanderson et al, 2015a). Similar incidences of release of mitochondrial OPA1 and cytochrome c followed by apoptosis were observed in primary rat neuronal cells in a simulated model of ischemia-reperfusion hypoxic injury (Sanderson et al, 2015b). These results from at least two different models of neuronal injury suggest that increased oxidative stress is involved in regulating the mitochondrial fusion and fission process and cell death, although the detailed mechanism by which increased oxidative stress stimulates OPA1 release from mitochondria needs to be further studied.…”

“…Consequently, an ischemic condition in brain severely suppresses metabolic processes and generates energy crisis with decreased visual, cognitive and neuromuscular functions. It is likely that the suppressed neuromuscular and cognitive functions can be attributed to mitochondrial dysfunctions either through hypoxia-mediated decreased levels of mitochondrial fusion (Sanderson et al, 2015b) and/or increased oxidative stress (Sun et al, 2014), which can impair mitochondrial function by promoting various PTMs of mitochondrial proteins and oxidative mitochondrial DNA damage. By using a specific peptide inhibitor of JNK, Nijboer and colleagues also demonstrated an important role of mitochondrial JNK in causing neuroinflammation and neuronal damage under ischemic hypoxia (Nijboer et al, 2013), as similar to an acute liver injury by exposure to a hepatotoxin carbon tetrachloride (Moon et al, 2010; Jang et al, 2015) or following hepatic ischemia reperfusion (Moon et al, 2008).…”

AMPK: keeping the (power)house in order?

“…Fission occurs as an early event in a number of neurodegenerative diseases including Alzheimer's disease [26] and Huntington's disease [27] as well as occurring after brain trauma such as stroke or neonatal hypoxic-ischaemic injury [28,29], environments in which AMPK is known to be activated [30][31][32]. Indeed, inhibitors of post-injury fission, such as mDivi-1 and p110, have proved successful as neuroprotectants.…”