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Role of apoptosis-inducing factor (Aif) in the T cell lineage.

Prabhu SB, Khalsa JK, Banerjee H, Das A, Srivastava S, Mattoo HR, Thyagarajan K, Tanwar S, Das DS, Majumdar SS, George A, Bal V, Durdik JM, Rath S - Indian J. Med. Res. (2013)

Bottom Line: During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS).In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID).Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Immunology, New Delhi, India, .

ABSTRACT
Multiple checkpoints regulating finely balanced death-versus-survival decisions characterize both thymic development and peripheral homeostasis of T lymphocytes. While exploring the mechanisms of T cell death involved at various stages during the life of a T cell, we have observed and reported a variety of non-redundant roles for apoptosis inducing factor (Aif), a mitochondrial flavoprotein. Aif is ubiquitously expressed in all cell lineages and functions as an NADH oxidase in its mitochondrial location. It is released following the mitochondrial death signals, whereupon it translocates to the nucleus, binds to DNA and causes large-scale DNA fragmentation. During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS). In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID). Thus, Aif seems to have pro-apoptotic and anti-apoptotic roles in the same lineage in different contexts and at different stages. Surprisingly, in the closely related B lymphocyte lineage, Aif deficiency does not result in any abnormality. These findings generate the possibility of specific T cell dysfunction in human disease caused by Aif deficiency, as well as in mitochondriopathies due to other causes. Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.

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Potential role of Aif in intrinsic pathway of apoptosis. During apoptosis, mitochondrial leakiness is mediated by two distinct pathways – mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT). MPT follows the cyclophilin dependent assembly of ANT and VDAC channels and results in release of death-effector molecules from inner membrane space, including Aif. In addition to its role in DNA binding and fragmentation, Aif amplifies further release of other effector molecules like cytochrome c from the mitochondria. MOMP is cyclophilin independent and release of effector molecules from inner mitochondrial space is mediated by Bax/Bak pores. (Adapted from Ref. 83). Key: Aif, apoptosis inducing factor; ANT, adenine nucleotide transporter; MPT, mitochondrial permeability transition; VDAC, voltage dependent anion channel; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; MOMP, mitochondrial outer membrane permeabilization; IMS, inter membrane space; Apaf-a, apoptosis protease activating factors-1.
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Figure 1: Potential role of Aif in intrinsic pathway of apoptosis. During apoptosis, mitochondrial leakiness is mediated by two distinct pathways – mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT). MPT follows the cyclophilin dependent assembly of ANT and VDAC channels and results in release of death-effector molecules from inner membrane space, including Aif. In addition to its role in DNA binding and fragmentation, Aif amplifies further release of other effector molecules like cytochrome c from the mitochondria. MOMP is cyclophilin independent and release of effector molecules from inner mitochondrial space is mediated by Bax/Bak pores. (Adapted from Ref. 83). Key: Aif, apoptosis inducing factor; ANT, adenine nucleotide transporter; MPT, mitochondrial permeability transition; VDAC, voltage dependent anion channel; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; MOMP, mitochondrial outer membrane permeabilization; IMS, inter membrane space; Apaf-a, apoptosis protease activating factors-1.

Mentions: Apoptosis-inducing factor was discovered as the first protein that regulates caspase-independent apoptosis4243. Aif is a flavoprotein that functions as an NADH oxidase and uses FAD as a co-factor44. In healthy cells Aif is N-terminally anchored to the inner mitochondrial membrane and remains confined to intermembrane space. Aif is synthesized as a 67 kDa protein and contains a mitochondrial localization signal in the N-terminus. In the mitochondria, a mitochondrial peptidase cleaves the N-terminal signal and the mature 62 kDa Aif protein is generated. Aif normally functions as a NADH oxidase and the crystal structure of Aif reveals an oxidoreductase-like folding. Aif- embryonic stem cells and HeLa cells show a quantitative reduction in complex I subunits along with reduction of complex I activity and a partial reduction in complex III activity. It is thus presumed that Aif is important for the structural and functional organization of complex I and probably of complex III45. In addition to the oxidoreductase function of Aif, it has a clear functional domain for DNA binding activity46. On receiving apoptotic signals, Aif is cleaved from the inner mitochondrial membrane, released out into the cytosol following mitochondrial outer membrane permeabilisation (MOMP) (Fig.), translocates into the nucleus, binds to DNA and causes widespread chromatin condensation and cleavage. The signals that cleave and release Aif into the cytosol are only partially elucidated, however, cysteine proteases including calpains and certain cathepsins are presumed to play an important role48. Oxidative stress and DNA damage leads to activation of Poly ADP ribose polymerase (PARP), a nuclear enzyme that synthesizes Poly ADP ribose (PAR) at the expense of ATP and NAD+49. Activated PARP triggers DNA repair and when cellular injury is extensive, can trigger apoptosis through various pathways. Aif is one of the effectors for PARP-mediated cellular death50. Aif leakage can be caspase-dependent or caspase-independent depending upon the context4251. Cytosolic Aif causes further damage to mitochondria and amplifies the release of Aif42.


Role of apoptosis-inducing factor (Aif) in the T cell lineage.

Prabhu SB, Khalsa JK, Banerjee H, Das A, Srivastava S, Mattoo HR, Thyagarajan K, Tanwar S, Das DS, Majumdar SS, George A, Bal V, Durdik JM, Rath S - Indian J. Med. Res. (2013)

Potential role of Aif in intrinsic pathway of apoptosis. During apoptosis, mitochondrial leakiness is mediated by two distinct pathways – mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT). MPT follows the cyclophilin dependent assembly of ANT and VDAC channels and results in release of death-effector molecules from inner membrane space, including Aif. In addition to its role in DNA binding and fragmentation, Aif amplifies further release of other effector molecules like cytochrome c from the mitochondria. MOMP is cyclophilin independent and release of effector molecules from inner mitochondrial space is mediated by Bax/Bak pores. (Adapted from Ref. 83). Key: Aif, apoptosis inducing factor; ANT, adenine nucleotide transporter; MPT, mitochondrial permeability transition; VDAC, voltage dependent anion channel; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; MOMP, mitochondrial outer membrane permeabilization; IMS, inter membrane space; Apaf-a, apoptosis protease activating factors-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928691&req=5

Figure 1: Potential role of Aif in intrinsic pathway of apoptosis. During apoptosis, mitochondrial leakiness is mediated by two distinct pathways – mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT). MPT follows the cyclophilin dependent assembly of ANT and VDAC channels and results in release of death-effector molecules from inner membrane space, including Aif. In addition to its role in DNA binding and fragmentation, Aif amplifies further release of other effector molecules like cytochrome c from the mitochondria. MOMP is cyclophilin independent and release of effector molecules from inner mitochondrial space is mediated by Bax/Bak pores. (Adapted from Ref. 83). Key: Aif, apoptosis inducing factor; ANT, adenine nucleotide transporter; MPT, mitochondrial permeability transition; VDAC, voltage dependent anion channel; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; MOMP, mitochondrial outer membrane permeabilization; IMS, inter membrane space; Apaf-a, apoptosis protease activating factors-1.
Mentions: Apoptosis-inducing factor was discovered as the first protein that regulates caspase-independent apoptosis4243. Aif is a flavoprotein that functions as an NADH oxidase and uses FAD as a co-factor44. In healthy cells Aif is N-terminally anchored to the inner mitochondrial membrane and remains confined to intermembrane space. Aif is synthesized as a 67 kDa protein and contains a mitochondrial localization signal in the N-terminus. In the mitochondria, a mitochondrial peptidase cleaves the N-terminal signal and the mature 62 kDa Aif protein is generated. Aif normally functions as a NADH oxidase and the crystal structure of Aif reveals an oxidoreductase-like folding. Aif- embryonic stem cells and HeLa cells show a quantitative reduction in complex I subunits along with reduction of complex I activity and a partial reduction in complex III activity. It is thus presumed that Aif is important for the structural and functional organization of complex I and probably of complex III45. In addition to the oxidoreductase function of Aif, it has a clear functional domain for DNA binding activity46. On receiving apoptotic signals, Aif is cleaved from the inner mitochondrial membrane, released out into the cytosol following mitochondrial outer membrane permeabilisation (MOMP) (Fig.), translocates into the nucleus, binds to DNA and causes widespread chromatin condensation and cleavage. The signals that cleave and release Aif into the cytosol are only partially elucidated, however, cysteine proteases including calpains and certain cathepsins are presumed to play an important role48. Oxidative stress and DNA damage leads to activation of Poly ADP ribose polymerase (PARP), a nuclear enzyme that synthesizes Poly ADP ribose (PAR) at the expense of ATP and NAD+49. Activated PARP triggers DNA repair and when cellular injury is extensive, can trigger apoptosis through various pathways. Aif is one of the effectors for PARP-mediated cellular death50. Aif leakage can be caspase-dependent or caspase-independent depending upon the context4251. Cytosolic Aif causes further damage to mitochondria and amplifies the release of Aif42.

Bottom Line: During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS).In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID).Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Immunology, New Delhi, India, .

ABSTRACT
Multiple checkpoints regulating finely balanced death-versus-survival decisions characterize both thymic development and peripheral homeostasis of T lymphocytes. While exploring the mechanisms of T cell death involved at various stages during the life of a T cell, we have observed and reported a variety of non-redundant roles for apoptosis inducing factor (Aif), a mitochondrial flavoprotein. Aif is ubiquitously expressed in all cell lineages and functions as an NADH oxidase in its mitochondrial location. It is released following the mitochondrial death signals, whereupon it translocates to the nucleus, binds to DNA and causes large-scale DNA fragmentation. During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS). In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID). Thus, Aif seems to have pro-apoptotic and anti-apoptotic roles in the same lineage in different contexts and at different stages. Surprisingly, in the closely related B lymphocyte lineage, Aif deficiency does not result in any abnormality. These findings generate the possibility of specific T cell dysfunction in human disease caused by Aif deficiency, as well as in mitochondriopathies due to other causes. Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.

Show MeSH
Related in: MedlinePlus