Editors' ChoicePhysiology

Long Life Through Damaged Mitochondria

Sci. Signal.  05 Nov 2013:
Vol. 6, Issue 300, pp. ec266
DOI: 10.1126/scisignal.2004879

Mild cellular injury can produce adaptive changes that enable resistance to subsequent stress. Owusu-Ansah et al. investigated the molecular responses of fruit flies to mild mitochondrial dysfunction, which initiates retrograde signaling to the nucleus and has been associated with extended life span. High temperature–inducible moderate knockdown of a component of the electron transport chain specifically in muscles (TDN) in larvae produced adult flies that were overall smaller with smaller muscles but exhibited increased life span and longer climbing ability than did control flies exposed to the same temperatures (TD). Forced expression of enzymes that metabolize reactive oxygen species (ROS) eliminated the enhanced life span and locomotor activity of the TDN flies. A screen for genes that when knocked down resulted in synthetic lethality in the TDN flies identified genes encoding proteins involved in the mitochondrial unfolded protein response (UPRmt), indicating that this pathway was involved in the adaptive response. Induction of mild mitochondrial dysfunction by TDN in adult flies increased life span and preserved the integrity of both muscles and muscle mitochondria compared with adult TD flies exposed to the same temperatures. Indeed, the TD adult flies exhibited substantial muscle degeneration when exposed to the same temperatures, and forced expression of genes associated with UPRmt prevented this high temperature–induced muscle degeneration. The redox-induced Jun N-terminal kinase (JNK) pathway was activated concurrently with the increase in genes associated with UPRmt in the TDN flies exposed to high temperature, and disrupting ROS signaling either by forced expression of catalase or by mutation of D-Jun prevented expression of the UPRmt-associated genes and life-span extension. Because TDN flies that were exposed to the temperature shift as larvae were overall smaller, the authors searched in the results of the synthetic lethal screen for genes encoding systemic factors that could affect growth and identified ImpL2, the Drosophila homolog of insulin-like growth factor binding protein 7 (IGFBP7). ImpL2 expression, along with downstream markers of suppression of insulin signaling, was increased in the thorax, abdomen, and head of TDN flies. Disruption of ImpL2 prevented the increase in longevity of the TDN flies, and its overexpression specifically in muscles was sufficient to extend life span. TDN muscles had an increased abundance of markers of autophagy and lysosomes. Electron microscopic analysis confirmed increased mitophagy (mitochondrial autophagy). Disruption of ImpL2 prevented the increase in lysosomes, and the disruption of genes associated with autophagy prevented the extension of life span in TDN flies. Thus, mild mitochondrial dysfunction activates autonomous and nonautonomous pathways that produce adaptive responses that extend life span.

E. Owusu-Ansah, W. Song, N. Perrimon, Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699–712 (2013). [Online Journal]

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