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Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast.

ABSTRACT: In mammalian cells, the autophagy-dependent degradation of mitochondria (mitophagy) is thought to maintain mitochondrial quality by eliminating damaged mitochondria. However, the physiological importance of mitophagy has not been clarified in yeast. Here, we investigated the physiological role of mitophagy in yeast using mitophagy-deficient atg32- or atg11-knock-out cells. When wild-type yeast cells in respiratory growth encounter nitrogen starvation, mitophagy is initiated, excess mitochondria are degraded, and reactive oxygen species (ROS) production from mitochondria is suppressed; as a result, the mitochondria escape oxidative damage. On the other hand, in nitrogen-starved mitophagy-deficient yeast, excess mitochondria are not degraded and the undegraded mitochondria spontaneously age and produce surplus ROS. The surplus ROS damage the mitochondria themselves and the damaged mitochondria produce more ROS in a vicious circle, ultimately leading to mitochondrial DNA deletion and the so-called "petite-mutant" phenotype. Cells strictly regulate mitochondrial quantity and quality because mitochondria produce both necessary energy and harmful ROS. Mitophagy contributes to this process by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production.

SUBMITTER: Kurihara Y

PROVIDER: S-EPMC3270981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleDiabetic patients develop cardiomyopathy characterized by hypertrophy, diastolic dysfunction, and intracellular lipid accumulation, termed lipotoxicity. Diabetic hearts utilize fatty acids as a major energy source, which produces high levels of oxidative stress, thereby inducing mitochondrial dysfunction.ObjectiveTo elucidate how mitochondrial function is regulated in diabetic cardiomyopathy.Methods and resultsMice were fed either a normal diet or high-fat diet (HFD, 60 kcal % fat). Although autophagic flux was activated by HFD consumption, peaking at 6 weeks ( P<0.05), it was attenuated thereafter. Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD feeding (mitophagy area: 8.3% per cell with normal diet and 12.4% with HFD) and continued to increase even after 2 months ( P<0.05). By isolating adult cardiomyocytes from GFP-LC3 mice fed HFD, we confirmed that mitochondria were sequestrated by LC3-positive autophagosomes during mitophagy. In wild-type mice, cardiac hypertrophy, diastolic dysfunction (end diastolic pressure-volume relationship =0.051±0.009 in normal diet and 0.11±0.004 in HFD) and lipid accumulation occurred within 2 months of HFD feeding ( P<0.05). Deletion of atg7 impaired mitophagy, increased lipid accumulation, exacerbated diastolic dysfunction (end diastolic pressure-volume relationship =0.11±0.004 in wild type and 0.152±0.019 in atg7 cKO; P<0.05) and induced systolic dysfunction (end systolic pressure-volume relationship =24.86±2.46 in wild type and 15.93±1.76 in atg7 cKO; P<0.05) during HFD feeding. Deletion of Parkin partially inhibited mitophagy, increased lipid accumulation and exacerbated diastolic dysfunction (end diastolic pressure-volume relationship =0.124±0.005 in wild type and 0.176±0.018 in Parkin KO, P<0.05) in response to HFD feeding. Injection of TB1 (Tat-Beclin1) activated mitophagy, attenuated mitochondrial dysfunction, decreased lipid accumulation, and protected against cardiac diastolic dysfunction (end diastolic pressure-volume relationship =0.110±0.009 in Control peptide and 0.078±0.015 in TB1, P<0.05) during HFD feeding.ConclusionsMitophagy serves as an essential quality control mechanism for mitochondria in the heart during HFD consumption. Impairment of mitophagy induces mitochondrial dysfunction and lipid accumulation, thereby exacerbating diabetic cardiomyopathy. Conversely, activation of mitophagy protects against HFD-induced diabetic cardiomyopathy.

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Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast.

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