The homeostatic link between the production of mitochondrial ROS (mtROS) and mitophagy plays a significant role in how cells respond to various physiological and pathological conditions. However, it remains unclear how cells translate oxidative stress signals into adaptive mitophagy responses. Here, we show that mtROS act as signaling molecules that activate the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway. When activated, CHK2 regulates three critical steps in mitophagy. First, CHK2 phosphorylates mitochondrial membrane protein ATAD3A at Ser371, which inhibits the transport of PINK1 to the inner mitochondrial membrane and leads to the accumulation of PINK1 and the commencement of mitophagy. Second, activated CHK2 targets the autophagy adaptor OPTN at Ser177 and Ser473, thereby enhancing the targeting of ubiquitinated mitochondria to autophagosomes. Finally, CHK2 phosphorylates Beclin 1 at Ser90 and Ser93, hence promoting the formation of autophagosomal membranes. Consistent with these effects, Chk2 ^−/− mice show impaired mitophagic induction and impaired recovery in a ROS-dependent model of renal ischemia–reperfusion. Our study reveals a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage.

Nrf2 acts as a transcriptional master regulator to orchestrate antioxidant responses and maintain redox balance. However, the cellular pathway for translating oxidative stress signals into Nrf2-dependent antioxidant responses remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules in modulating Nrf2’s stability and transcriptional activity by activating the DNA damage response (DDR) signaling pathway. When activated, CHK2 phosphorylates the autophagy adaptor protein p62 at serine-349, promoting its interaction with Keap1 and disrupting the Keap1-Nrf2 interaction, thereby inhibiting Nrf2 ubiquitination–dependent degradation. In addition, CHK2 directly phosphorylates Nrf2 at serine-566/serine-577, enhancing its transcriptional activity and antioxidant capacity. Consistent with these effects, Chk2 ^−/− mice show impaired expression of Nrf2 and its downstream antioxidant target genes, along with more severe renal tissue damage in an ROS-dependent model of renal ischemia/reperfusion injury. Our study reveals a direct mechanism linking the DDR signaling pathway to ROS-triggered Nrf2-dependent antioxidant responses, providing critical insight into cellular protection against oxidative stress–induced damage.

Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.

The really interesting new gene (RING) finger protein 8 (RNF8) is a central factor in DNA double strand break (DSB) signal transduction. DSB damage is the most toxic type of DNA damage to cells and is related to genomic instability. Multiple roles for RNF8 have been identified in DNA damage response as well as in other functions, such as telomere protection, cell cycle control and transcriptional regulation. These functions are closely correlated to tumorigenesis and cancer progression. Indeed, deficiency of RNF8 caused spontaneous tumorigenesis in a mouse model. Deciphering these mechanisms of RNF8 may shed light on strategies for cancer treatment. In this review, we summarize the current understanding of both classical and nonclassical functions of RNF8, and discuss its roles in the pathogenesis and progression of tumor.

It is emerging that autophagy-related proteins regulate the adaptive response to DNA damage in maintaining genome stability at multiple pathways. Here, we discuss recent insights into how autophagy-related proteins participate in DNA damage repair processes, influence chromosomal instability, and regulate the cell cycle through autophagy-dependent and independent actions. There is increasing awareness of the importance of these pathways mediated by autophagy-related proteins to DNA damage response (DDR), and disturbances in these regulatory connections may be linked to genomic instability participated in various human diseases, such as cancer and aging.

Low socioeconomic status (SES) is associated with increased chronic obstructive pulmonary disease (COPD) risk, with smoking and poor diet as major contributing factors. However, the impact of a comprehensive healthy lifestyle as a potential mediator between SES and COPD risk remains understudied. This study analyzed data from 32,836 US adults in the NHANES (1999–2020) and 131,872 UK adults in the UK Biobank. SES was assessed via latent class analysis based on income, education, employment, and health insurance (NHANES). SES was categorized into high, middle, and low levels. Healthy lifestyle scores included nonsmoking, no heavy drinking, regular physical activity, and a high-quality diet. Weighted multivariable logistic regression (NHANES) and Cox proportional hazards models (UK Biobank) were used to assess the associations between SES and the prevalence (NHANES) or incidence (UK Biobank) of COPD. In the UK Biobank, the incidences of newly diagnosed COPD in the high-, medium-, and low-SES groups were 1.27%, 2.92%, and 6.57%, respectively. In the U.S. NHANES, the prevalence rates of COPD were 2.55%, 2.53%, and 4.50%, respectively. Compared with the highest SES group, a low SES was a risk factor for both the incidence and prevalence of COPD (UK Biobank: HR = 3.27, 95% CI = 2.98 to 3.58; NHANES: OR = 1.61, 95% CI = 1.23 to 2.10). The percentages of the mediation effect of a healthy lifestyle in the UK Biobank and US NHANES were 2.81% and 37.27%, respectively. Additionally, compared with those in the group with the highest SES and the healthiest lifestyle, the risk of COPD incidence and prevalence increased by 950% (HR = 10.50, 95% CI = 9.04 to 12.20) and 641% (OR = 7.41, 95% CI = 5.10 to 10.78), respectively, in the group with the lowest SES and the unhealthiest lifestyle. Risk factor analysis for COPD revealed that, in addition to a low SES (HR = 2.55, 95% CI = 2.39 to 2.72; OR = 2.08, 95% CI = 1.76 to 2.46) and unhealthy lifestyle (HR = 2.92, 95% CI = 2.73 to 3.12; OR = 3.78, 95% CI = 3.13 to 4.57), smoking (HR = 5.23, 95% CI = 4.87 to 5.61; OR = 3.85, 95% CI = 3.23 to 4.59) was the most significant risk factor for COPD. Low SES significantly contributes to COPD risk, but a healthy lifestyle mediating this association. Promoting healthy lifestyle choices and addressing socioeconomic disparities are essential public health strategies for COPD prevention. Additionally, smoking cessation and increased early screening in smokers are strongly recommended.