Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology

Abstract

Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host–cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.

Moderate-intensity aerobic exercise training improves CD8+ tumor-infiltrating lymphocytes effector function by reducing mitochondrial loss

“…However, the total TILs protein expression of dynamin-like GTPase Mitofusin 1 (Mfn1), essential for mitochondrial fusion, 28 was not different between the groups ( Figure S3 A). In addition, no significant differences were observed in the gene expression of PINK1, PARK2, ULK1, BNIP3, ATG5, ATG7, and LC3B, markers of autophagy/mitophagy, 29 , 30 in the solid tumors of CT26 TR compared to CT26 SED mice ( Figures S3 B–S3H).

Figure 6 Increased IFNγ production in CD8 + TILs promoted by aerobic exercise training is associated with improved mitochondrial density and function (A) Mitochondrial number per cell, (B–D) area, elongation, and circularity of CD8 + TILs isolated using magnetic beads, and (E) representative transmission electron microscopy images, (F) CD8 + TILs mitochondrial density evaluated by the MitoTracker Green fluorescent probe, (G) and compared to the mitochondrial density of inguinal lymph node CD8 + T cells harvested from healthy sedentary controls (white bars), (H and I) the ratio between CD8 + TILs with high and low mitochondrial membrane potential (healthy and unhealthy mitochondria, respectively) evaluated by the JC-1 fluorescent probe, and (J) ATP production by total tumor-infiltrating leukocytes comparing sedentary tumor-bearing mice (CT26 SED) and trained tumor-bearing mice (CT26 TR).

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