Complex IV-deficient Surf1−/− mice initiate mitochondrial stress responses

Abstract

Summary Mutations in SURF1 cytochrome c oxidase (COX) assembly protein are associated with Leigh’s syndrome, a human mitochondrial disorder that manifests as severe mitochondrial phenotypes and early lethality. In contrast, mice lacking the Surf1 protein (Surf1−/−) are viable and were previously shown to have enhanced longevity and a greater than 50% reduction in COX activity. We measured mitochondrial function in heart and skeletal muscle, and despite the significant reduction in COX activity, we found little or no difference in reactive oxygen species (ROS) generation, membrane potential, ATP production or respiration in isolated mitochondria from Surf1−/− mice compared to wild-type. However, blood lactate levels are elevated and Surf1−/− mice have reduced running endurance, suggesting compromised mitochondrial energy metabolism in vivo. Decreased COX activity in Surf1−/− mice is associated with increased markers of mitochondrial biogenesis (PGC-1α and VDAC) in both heart and skeletal muscle. While mitochondrial biogenesis is a common response in the two tissues, skeletal muscle have an up-regulation of the mitochondrial unfolded protein response (UPRMT) and heart exhibits induction of the Nrf2 antioxidant response pathway. These data are the first to report induction of the UPRMT in a mammalian model of diminished COX activity. In addition our results suggest that impaired mitochondrial function can lead to induction of mitochondrial stress pathways to confer protective effects on cellular homeostasis. Loss of complex IV assembly factor Surf1 in mice results in compensatory responses including mitochondrial biogenesis, the nrf2 pathway and the mitochondrial unfolded protein response. This compensatory response may contribute to the lack of deleterious phenotypes under basal conditions.

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

“…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

“…Surf1 deficiency was previously reported to lead to a reduction in COX activity, without affecting activity of other ETC complexes (Dell'agnello et al., 2007; Pulliam et al., 2014). Here, we measured COX activity in liver, heart, and white adipose tissue (WAT) of young (8–12 months) and old (24–27 months) Surf1 −/− and Surf1 +/+ female mice using tissue homogenates.…”

“…(c) Sleep fragmentation in 28‐month‐old Surf1 +/+ (black bars) and Surf1 −/− (white bars) female fed AL expressed as the number of sleep bouts per hour of sleep (any period of inactivity (no beam breaks) greater than or equal to 40 s). (d) Spontaneous activity measured in AL‐fed 28‐month‐old Surf1 +/+ (black bars) and Surf1 −/− (white bars) mice measured as the number of beam breaks (e) Cardiovascular functions end systolic dimension (left panel) and fractional shortening (right panel) in 20‐month‐old Surf1 +/+ (black bars) and Surf1 −/− (white bars) female mice measured as previously described (Pulliam et al., 2014). Error bars represent mean ±  SEM …”

“…Surf1 −/− male mice are reported to have elevated mitochondrial biogenesis and increased expression of ETC subunits (Pulliam et al., 2014). Here, assessment of transcript levels of ETC subunits in liver of female Surf1 −/− and Surf1 +/+ mice showed that transcript levels of ETC subunits NDUFS3 (3.8‐fold), ND1 (2.2‐fold), SDHA (3.9‐fold), SDHB (3.2‐fold), Reiske protein (3.5‐fold), COX2 (2.3‐fold), and ATPase 6 (1.6‐fold) were significantly elevated in young Surf1 −/− mice (Figure S1e).…”

“…In addition, tissues from Surf1 −/− mice show increased mitochondrial biogenesis and induction of the mitochondrial unfolded protein response (UPRmt), an evolutionarily conserved stress response pathway (Baker, Tatsuta & Langer, 2011). Fibroblasts from Surf1 −/− mice also show increased resistance to cellular stresses (Pharaoh et al, 2016; Pulliam et al., 2014) suggesting that reduced COX activity induces compensatory mitochondrial stress response pathways.…”