bims-mitpro 2023-10-29 papers

Issue of 2023–10–29
four papers selected by
Andreas Kohler, Umeå University

Autophagy. 2023 Oct 24.

Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.

Kun Gao, Yingji Chen, Ren Mo, Chenji Wang.

Mitophagy, the process of removing damaged mitochondria to promote cell survival, plays a crucial role in cellular functionality. However, excessive, or uncontrolled mitophagy can lead to reduced mitochondrial content that burdens the remaining organelles, triggering mitophagy-mediated cell death. FBXL4 mutations, which affect the substrate-binding adaptor of the CUL1 (cullin 1)-RING ubiquitin ligase complex (CRL1), have been linked to mitochondrial DNA depletion syndrome type 13 (MTDPS13) characterized by reduced mtDNA content and impaired energy production in affected organs. However, the mechanism behind FBXL4 mutation-driven MTDPS13 remain poorly understood. In a recent study, we demonstrate that the CRL1-FBXL4 complex promotes the degradation of BNIP3 and BNIP3L, two key mitophagy cargo receptors. Deficiency of FBXL4 results in a strong accumulation of BNIP3 and BNIP3L proteins and triggers high levels of BNIP3- and BNIP3L-dependent mitophagy. Patient-derived FBXL4 mutations do not affect its interaction with BNIP3 and BNIP3L but impair the assembly of an active CRL1-FBXL4 complex. Furthermore, excessive mitophagy is observed in knockin mice carrying a patient-derived FBXL4 mutation, and in cortical neurons generated from human patient induced pluripotent stem cells (hiPSCs). These findings support the model that the CRL1-FBXL4 complex tightly restricts basal mitophagy, and its dysregulation leads to severe symptoms of MTDPS13.

Keywords: Lysosome; mitochondria; mitophagy; multi-system disorder; ubiquitination

DOI: https://doi.org/10.1080/15548627.2023.2274260

Mol Cancer Res. 2023 Oct 25.

Mitochondrial translocase TOMM22 is overexpressed in pancreatic cancer and promotes aggressive growth by modulating mitochondrial protein import and function.

Mary Oluwadamilola Haastrup, Kunwar Somesh Vikramdeo, Shashi Anand, Mohammad Aslam Khan, James Elliot Carter, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta.

Pancreatic cancer has the worst prognosis among all cancers underscoring the need for improved management strategies. Dysregulated mitochondrial function is a common feature in several malignancies, including pancreatic cancer. Although mitochondria have their own genome, most mitochondrial proteins are nuclear-encoded and imported by a multi-subunit translocase of the outer mitochondrial membrane (TOMM). TOMM22 is the central receptor of the TOMM complex and plays a role in complex assembly. Pathobiological roles of TOMM subunits remain largely unexplored. Here we report that TOMM22 protein/mRNA is overexpressed in pancreatic cancer and inversely correlated with disease outcomes. TOMM22 silencing decreased, while its forced overexpression promoted the growth and malignant potential of the pancreatic cancer cells. Increased import of several mitochondrial proteins, including those associated with mitochondrial respiration, was observed upon TOMM22 overexpression which was associated with increased RCI activity, NAD+/NADH ratio, oxygen consumption rate, membrane potential, and ATP production. Inhibition of RCI activity decreased ATP levels and suppressed pancreatic cancer cell growth and malignant behavior confirming that increased TOMM22 expression mediated the phenotypic changes via its modulation of mitochondrial protein import and functions. Altogether, these results suggest that TOMM22 overexpression plays a significant role in pancreatic cancer pathobiology by altering mitochondrial protein import and functions. Implications: TOMM22 bears potential for early diagnostic/prognostic biomarker development and therapeutic targeting for better management of pancreatic cancer patients.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0138

Nat Commun. 2023 Oct 23. 14(1): 6721

The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.

Hakjoo Lee, Tae Jin Lee, Chad A Galloway, Wenbo Zhi, Wei Xiao, Karen L de Mesy Bentley, Ashok Sharma, Yong Teng, Hiromi Sesaki, Yisang Yoon.

Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.

DOI: https://doi.org/10.1038/s41467-023-42564-0

Autophagy. 2023 Oct 24.

The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.

Yu Song, Huaizhen Liang, Gaocai Li, Liang Ma, Dingchao Zhu, Weifeng Zhang, Bide Tong, Shuai Li, Yong Gao, Xinghuo Wu, Yukun Zhang, Xiaobo Feng, Kun Wang, Cao Yang.

Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and mitophagy, but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zn2+ trafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs.

Keywords: Intervertebral disc degeneration; NLRX1; SLC39A7; mitochondrial dynamics; mitophagy; nucleus pulposus

DOI: https://doi.org/10.1080/15548627.2023.2274205