Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice

Abstract

Leigh syndrome associated with cytochrome c oxidase (COX) deficiency is a mitochondrial disorder usually caused by mutations of SURF1, a gene encoding a putative COX assembly factor. We present here a Surf1-/- recombinant mouse obtained by inserting a loxP sequence in the open reading frame of the gene. The frequency of -/-, +/+ and +/- genotypes in newborn mice followed a mendelian distribution, indicating that the ablation of Surf1 is compatible with postnatal survival. The biochemical and assembly COX defect was present in Surf1(loxP)-/- mice, but milder than in humans. Surprisingly, not only these animals failed to show spontaneous neurodegeneration at any age, but they also displayed markedly prolonged lifespan, and complete protection from Ca(2+)-dependent neurotoxicity induced by kainic acid. Experiments on primary neuronal cultures showed markedly reduced rise of cytosolic and mitochondrial Ca(2+) in Surf1(loxP)-/- neurons, and reduced mortality, compared to controls. The mitochondrial membrane potential was unchanged in KO versus wild-type neurons, suggesting that the effects of the ablation of Surf1 on Ca(2+) homeostasis, and possibly on longevity, may be independent, at least in part, from those on COX assembly and mitochondrial bioenergetics.

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…In a paradoxical way, in yeast (Delaney et al., 2013), worms (Dillin et al., 2002), flies (Owusu‐Ansah, Song & Perrimon, 2013), and mice (Liu et al., 2005), suppression of mitochondrial ETC function increases lifespan (Dell'agnello et al., 2007; Durieux, Wolff & Dillin, 2011). While counterintuitive, these findings are supported by reports demonstrating that upregulation of mitochondrial stress response contributes to enhanced longevity in the long‐lived mitochondrial mutants (Durieux et al., 2011; Kirchman, Kim, Lai & Jazwinski, 1999).…”

“…RNAi knockdown of either UBL5 or DVE1 (mediators of mtUPR) reversed lifespan extension in both mutants. Similar to that, increased longevity by muscle‐specific disruption of ETC Complex I in Drosophila was dependent on mtUPR (Owusu‐Ansah et al., 2013), and Surf1 knockout mice deficient for ETC Complex IV had increased expression of mtUPR genes (Dell'agnello et al., 2007; Pulliam et al., 2014). It is important that, a number of other pro‐longevity models, such as NAD+/Sirtuin1 or rapamycin in C. elegans , also require mtUPR (Houtkooper et al., 2013; Owusu‐Ansah et al., 2013).…”

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

“…In contrast, a study by Dell'agnello et al. (2007) reported that mice lacking expression of the Surf1 gene, which codes for the SURF1 assembly protein for complex IV (cytochrome c oxidase, COX) of the electron transport chain (Zhu et al., 1998), show a significant increase in mean lifespan despite a dramatic reduction in COX activity (Dell'agnello et al., 2007). These studies support the concept that mitochondrial function and lifespan are not causally linked.…”

“…Mice lacking active SURF1 protein ( Surf1 −/− mice) were developed to study Leigh Syndrome (Dell'agnello et al., 2007). However, despite reduced COX activity in all tissues, the Surf1 −/− mice exhibited an unexpected increase in lifespan and a number of phenotypes that do not seem consistent with reduced mitochondrial ETC activity.…”

“…However, despite reduced COX activity in all tissues, the Surf1 −/− mice exhibited an unexpected increase in lifespan and a number of phenotypes that do not seem consistent with reduced mitochondrial ETC activity. For example, Surf1 −/− mice are protected from kainic acid‐induced neuronal damage, and isolated neurons from Surf1 −/− mice are resistant to cytotoxic effects of glutamate (Dell'agnello et al., 2007). Studies from our laboratory have shown that Surf1 −/− mice have reduced fat mass, improved insulin sensitivity, and enhanced memory, compared to wild‐type ( Surf1 +/+ ) mice (Deepa et al., 2013; Lin et al., 2013).…”